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Journal articles on the topic 'HHIPL1'

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Author: Grafiati

Published: 10 December 2022

Last updated: 28 January 2023

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1

Aravani, Dimitra, Elisavet Karamanavi, Sarah L. Andrews, Nilesh J. Samani, Emma J. Stringer, and Thomas R. Webb. "A The Coronary Artery Disease Associated Gene HHIPL1 Promotes Atherosclerosis." Heart 102, Suppl 6 (June 2016): A145—A146. http://dx.doi.org/10.1136/heartjnl-2016-309890.220.

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2

Aravani, Dimitra, Gavin E. Morris, Peter D. Jones, Helena K. Tattersall, Elisavet Karamanavi, Michael A. Kaiser, Renata B. Kostogrys, et al. "HHIPL1 , a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis." Circulation 140, no. 6 (August 6, 2019): 500–513. http://dx.doi.org/10.1161/circulationaha.119.041059.

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3

Duong, Cuong V., Richard D. Emes, Frank Wessely, Kiren Yacqub-Usman, Richard N. Clayton, and William E. Farrell. "Quantitative, genome-wide analysis of the DNA methylome in sporadic pituitary adenomas." Endocrine-Related Cancer 19, no. 6 (October 8, 2012): 805–16. http://dx.doi.org/10.1530/erc-12-0251.

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DNA methylation is one of the several epigenetic modifications that together with genetic aberrations are hallmarks of tumorigenesis including those emanating from the pituitary gland. In this study, we examined DNA methylation across 27 578 CpG sites spanning more than 14 000 genes in the major pituitary adenoma subtypes. Genome-wide changes were first determined in a discovery cohort comprising non-functioning (NF), growth hormone (GH), prolactin (PRL)-secreting and corticotroph (CT) adenoma relative to post-mortem pituitaries. Using stringent cut-off criteria, we validated increased methylation by pyrosequencing in 12 of 16 (75%) genes. Overall, these criteria identified 40 genes in NF, 21 in GH, six in PRL and two in CT that were differentially methylated relative to controls. In a larger independent cohort of adenomas, for genes in which hypermethylation had been validated, different frequencies of hypermethylation were apparent, where the KIAA1822 (HHIPL1) and TFAP2E genes were hypermethylated in 12 of 13 NF adenomas whereas the COL1A2 gene showed an increase in two of 13 adenomas. For genes showing differential methylation across and between adenoma subtypes, pyrosequencing confirmed these findings. In three of 12 genes investigated, an inverse relationship between methylation and transcript expression was observed where increased methylation of EML2, RHOD and HOXB1 is associated with significantly reduced transcript expression. This study provides the first genome-wide survey of adenoma, subtype-specific epigenomic changes and will prove useful for identification of biomarkers that perhaps predict or characterise growth patterns. The functional characterisation of identified genes will also provide insight of tumour aetiology and identification of new therapeutic targets.

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4

Holtz, Alexander M., Samuel C. Griffiths, Samantha J. Davis, Benjamin Bishop, Christian Siebold, and Benjamin L. Allen. "Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function." Journal of Cell Biology 209, no. 5 (June 8, 2015): 739–58. http://dx.doi.org/10.1083/jcb.201411024.

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Vertebrate Hedgehog (HH) signaling is controlled by several ligand-binding antagonists including Patched-1 (PTCH1), PTCH2, and HH-interacting protein 1 (HHIP1), whose collective action is essential for proper HH pathway activity. However, the molecular mechanisms used by these inhibitors remain poorly understood. In this paper, we investigated the mechanisms underlying HHIP1 antagonism of HH signaling. Strikingly, we found evidence that HHIP1 non–cell-autonomously inhibits HH-dependent neural progenitor patterning and proliferation. Furthermore, this non–cell-autonomous antagonism of HH signaling results from the secretion of HHIP1 that is modulated by cell type–specific interactions with heparan sulfate (HS). These interactions are mediated by an HS-binding motif in the cysteine-rich domain of HHIP1 that is required for its localization to the neuroepithelial basement membrane (BM) to effectively antagonize HH pathway function. Our data also suggest that endogenous, secreted HHIP1 localization to HS-containing BMs regulates HH ligand distribution. Overall, the secreted activity of HHIP1 represents a novel mechanism to regulate HH ligand localization and function during embryogenesis.

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5

Freixas, Xavier, and Cornelia Holthausen. "Interbank Market Integration under Asymmetric Information." Review of Financial Studies 18, no. 2 (August 18, 2004): 459–90. http://dx.doi.org/10.1093/rfs/hhi001.

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6

Liu, Jun, Jun Pan, and Tan Wang. "An Equilibrium Model of Rare-Event Premia and Its Implication for Option Smirks." Review of Financial Studies 18, no. 1 (November 3, 2004): 131–64. http://dx.doi.org/10.1093/rfs/hhi011.

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7

Post, Thierry, and Haim Levy. "Does Risk Seeking Drive Stock Prices? A Stochastic Dominance Analysis of Aggregate Investor Preferences and Beliefs." Review of Financial Studies 18, no. 3 (2005): 925–53. http://dx.doi.org/10.1093/rfs/hhi021.

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8

Gervais, Simon, Anthony W. Lynch, and David K. Musto. "Fund Families as Delegated Monitors of Money Managers." Review of Financial Studies 18, no. 4 (2005): 1139–69. http://dx.doi.org/10.1093/rfs/hhi031.

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9

Liang, Guangchao, and Charles Edwin Webster. "Phosphoramidate hydrolysis catalyzed by human histidine triad nucleotide binding protein 1 (hHint1): a cluster-model DFT computational study." Org. Biomol. Chem. 15, no. 40 (2017): 8661–68. http://dx.doi.org/10.1039/c7ob02098h.

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10

Lao, Taotao, Zhiqiang Jiang, Jeong Yun, Weiliang Qiu, Feng Guo, Chunfang Huang, John Dominic Mancini, et al. "Hhip haploinsufficiency sensitizes mice to age-related emphysema." Proceedings of the National Academy of Sciences 113, no. 32 (July 21, 2016): E4681—E4687. http://dx.doi.org/10.1073/pnas.1602342113.

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Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip+/−), we observed increased lung compliance and spontaneous emphysema in Hhip+/− mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip+/− vs. Hhip+/+ mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip+/− mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip+/− mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip+/− mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.

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11

Zuo, Yun, Yan Lv, Xiaolan Qian, Shaokai Wang, Zhipen Chen, Qin Jiang, Cong Cao, and Yu Song. "Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration." Cellular Physiology and Biochemistry 45, no. 5 (2018): 1840–50. http://dx.doi.org/10.1159/000487875.

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Background/Aims: Human hedgehog-interacting protein (HHIP) is a negative regulator of the hedgehog (HH) signaling pathway. It is deregulated in gastric cancer. The underlying molecular mechanism of HHIP-induced inhibition of HH signaling remains to be determined. Methods: A lentiviral HHIP expression vector (“LV-HHIP”) was established to exogenously over-express HHIP in gastric cancer cells. HHIP protein and mRNA were tested by Western blotting assay and quantitative real-time PCR assay, respectively. Cell survival was tested by the Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was examined by the BrdU ELISA assay and [H3] Thymidine DNA incorporation assay. Cell invasion and migration were tested by the phagokinetic track assay and the “Transwell” assay. The bisulfite-sequencing PCR was applied to test HHIP promoter methylation. Results: In the established (AGS cell line) and primary human gastric cancer cells, LV-HHIP transfection increased HHIP expression and inhibited cancer cell survival and proliferation as well as cell migration and invasion. Furthermore, LV-HHIP significantly attenuated promoter methylation of the endogenous HHIP gene in AGS cells, causing it upregulation. Inhibition of methylation by 5-aza-dc similarly induced HHIP expression in gastric cancer cells, which inhibited cancer cell proliferation and migration. Conclusions: Our results suggest that inhibition of HHIP promoter methylation can efficiently inhibit human gastric cancer cell proliferation and migration.

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12

Zhou, Xin, Yanping Wang, Wenyun Chen, Hongmin Zhang, Yirui He, Han Dai, Wenjing Hu, et al. "Circulating HHIP Levels in Women with Insulin Resistance and PCOS: Effects of Physical Activity, Cold Stimulation and Anti-Diabetic Drug Therapy." Journal of Clinical Medicine 12, no. 3 (January 22, 2023): 888. http://dx.doi.org/10.3390/jcm12030888.

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Serum human hedgehog-interacting protein (HHIP) concentration is associated with diabetes. However, the relationship between HHIP and polycystic ovary syndrome (PCOS) or abnormal sex hormones remains unknown. This study was an observational cross-sectional study, with additional short-term intervention studies and follow-up studies. Bioinformatics analysis was performed to explore the association of PCOS with metabolic-related genes and signaling pathways. OGTT and EHC were performed on all participants. Lipid infusion, cold exposure, and 45-min treadmill test were performed on all healthy women. A total of 137 women with PCOS were treated with metformin, GLP-1RA, or TZDs for 24 weeks. Serum HHIP levels were higher in insulin resistance (IR) and PCOS women. Circulating HHIP levels were significantly correlated with adiponectin (Adipoq) levels, obesity, IR, and metabolic indicators. A correlation presented between HHIP and DHEA-S, FAI, SHBG, and FSH. Serum HHIP levels were significantly elevated by oral glucose challenge in healthy women, but not affected by EHC. Lipid infusion decreased serum HHIP levels, while cold exposure increased HHIP levels in healthy women. GLP-1RA and TZD treatment reduced serum HHIP levels in PCOS women, while metformin treatment did not affect HHIP levels. HHIP may be a useful biomarker and novel drug target for PCOS and IR individuals.

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13

Holtz, Alexander M., Samuel Charles Griffiths, Samantha Davis, Benjamin Bishop, Christian Siebold, and Benjamin L. Allen. "Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function." Journal of Experimental Medicine 212, no. 7 (June 29, 2015): 2127OIA55. http://dx.doi.org/10.1084/jem.2127oia55.

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14

Chou, Hsuan-Wen, Hao-Chang Hung, Ching-Han Lin, An-Chi Lin, Ye-Fong Du, Kai-Pi Cheng, Chung-Hao Li, Chih-Jen Chang, Hung-Tsung Wu, and Horng-Yih Ou. "The Serum Concentrations of Hedgehog-Interacting Protein, a Novel Biomarker, Were Decreased in Overweight or Obese Subjects." Journal of Clinical Medicine 10, no. 4 (February 12, 2021): 742. http://dx.doi.org/10.3390/jcm10040742.

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Although it was known that obesity is an independent risk factor for metabolic disorders including diabetes, the factors that link these diseases were obscure. The Hedgehog-interacting protein (Hhip) is a negative regulator in tissue remodeling, and inhibits the proliferation of adipocytes, and promotes their differentiation. In addition, Hhip was positively associated with diabetes. However, the relationship between Hhip and obesity in the human body remains unclear. An analysis of the relationship between Hhip and normal weight, overweight, and obesity levels. Participants receiving a physical checkup were recruited. Anthropometric and biochemical data were collected. Serum Hhip levels were determined by enzyme-linked immunosorbent assay (ELISA). Subjects were classified into normal-weight, overweight, and obese groups based on their body mass index (BMI). The association between Hhip and obesity was examined by multivariate linear regression analysis. In total, 294 subjects who were either of a normal weight (n = 166), overweight (n = 90), or obese (n = 38) were enrolled. Hhip concentrations were 6.51 ± 4.86 ng/mL, 5.79 ± 4.33 ng/mL, and 3.97 ± 3.4 ng/mL in normal-weight, overweight, and obese groups, respectively (p for trend = 0.032). Moreover, the regression analysis showed that BMI (β = −0.144, 95% confidence interval (CI) = −0.397−0.046, p = 0.013) was negatively associated with Hhip concentrations after adjusting for sex and age. Being overweight (β = −0.181, 95% CI = −3.311−0.400, p = 0.013) and obese (β = −0.311, 95% CI = −6.393−2.384, p < 0.001) were independently associated with Hhip concentrations after adjusting for sex, age, fasting plasma glucose, the insulin level, and other cardiometabolic risk factors. Our results showed that overweight and obese subjects had lower Hhip concentrations than those of normal weight. Being overweight and obese were negatively associated with Hhip concentrations. Hhip might be a link between obesity and diabetes.

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15

Wu, Yueh-Lung, Carol P. Wu, Song-Tay Lee, Han Tang, Chi-Hua Chang, Hong-Hwa Chen, and Yu-Chan Chao. "The Early Gene hhi1 Reactivates Heliothis zea Nudivirus 1 in Latently Infected Cells." Journal of Virology 84, no. 2 (November 4, 2009): 1057–65. http://dx.doi.org/10.1128/jvi.01548-09.

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ABSTRACT Heliothis zea nudivirus 1 (HzNV-1), previously known as Hz-1 virus, is an insect virus able to establish both productive and latent infections in several lepidopteran insect cells. Here, we have cloned and characterized one of the HzNV-1 early genes, hhi1, which maps to the HindIII-I fragment of the viral genome. During the productive viral infection, a 6.2-kb hhi1 transcript was detectable as early as 0.5 h postinfection (hpi). The level of transcript reached a maximum at 2 hpi and gradually decreased after 4 hpi. The transcript was not detectable during the latent phase of viral infection. Upon cycloheximide treatment, much higher levels of hhi1 transcript were detected throughout the productive viral infection cycle, suggesting that newly synthesized proteins are not needed for the expression of hhi1. Nevertheless, viral coinfection can further stimulate the expression of transfected hhi1 promoter in a plasmid. Transient hhi1 expression in latently infected cells resulted in a significant increase in virus titer and viral DNA propagation, suggesting that hhi1 plays a critical role in viral reactivation. Additional experiments showed that six early genes, which possibly function in transcription or DNA replication, were activated in the latent cells upon hhi1 transfection. Among these six genes, orf90 and orf121 expression could be induced by hhi1 alone without the need for other viral genes. Our discovery should be useful for future mechanistic study of the switches of latent/productive HzNV-1 viral infections.

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Qin, Qianyi, Haoqing Yang, Chen Zhang, Xiao Han, Jing Guo, Zhipeng Fan, and Jie Guo. "lncRNA HHIP-AS1 Promotes the Osteogenic Differentiation Potential and Inhibits the Migration Ability of Periodontal Ligament Stem Cells." Stem Cells International 2021 (April 26, 2021): 1–12. http://dx.doi.org/10.1155/2021/5595580.

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Alveolar bone remodeling under orthodontic force is achieved by periodontal ligament stem cells (PDLSCs), which are sensitive to mechanical loading. How to regulate functions of PDLSCs is a key issue in bone remodeling during orthodontic tooth movement. This study is aimed at investigating the roles of lncRNA Hedgehog-interacting protein antisense RNA 1 (HHIP-AS1) in the functional regulation of PDLSCs. First, HHIP-AS1 expression was downregulated in PDLSCs under continuous compressive pressure. Then, we found that the alkaline phosphatase activity, in vitro mineralization, and expression levels of bone sialoprotein, osteocalcin, and osterix were increased in PDLSCs by HHIP-AS1. The results of scratch migration and transwell chemotaxis assays revealed that HHIP-AS1 inhibited the migration and chemotaxis abilities of PDLSCs. In addition, the RNA sequencing data showed that 356 mRNAs and 14 lncRNAs were upregulated, including receptor tyrosine kinase-like orphan receptor 2 and nuclear-enriched abundant transcript 1, while 185 mRNAs and 6 lncRNAs were downregulated, including fibroblast growth factor 5 and LINC00973, in HHIP-AS1-depleted PDLSCs. Bioinformatic analysis revealed several biological processes and signaling pathways related to HHIP-AS1 functions, including the PI3K-Akt signaling pathway and JAK-STAT signaling pathway. In conclusion, our findings indicated that HHIP-AS1 was downregulated in PDLSCs under compressive pressure, and it promoted the osteogenic differentiation potential and inhibited the migration and chemotaxis abilities of PDLSCs. Thus, HHIP-AS1 may be a potential target for accelerating tooth movement during orthodontic treatment.

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Lin, Hung, Chen, Cheng, Li, Lin, Chang, Wu, and Ou. "Elevated Hedgehog-Interacting Protein Levels in Subjects with Prediabetes and Type 2 Diabetes." Journal of Clinical Medicine 8, no. 10 (October 6, 2019): 1635. http://dx.doi.org/10.3390/jcm8101635.

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Background: The prevalence of diabetes is rapidly increasing worldwide and is highly associated with the incidence of cancers. In order to prevent diabetes, early diagnosis of prediabetes is important. However, biomarkers for prediabetes diagnosis are still scarce. The hedgehog-interacting protein (Hhip) is important in embryogenesis and is known to be a biomarker of several cancers. However, Hhip levels in subjects with diabetes are still unknown. Methods: In total, 314 participants were enrolled and divided into normal glucose tolerance (NGT; n = 75), impaired fasting glucose (IFG; n = 66), impaired glucose tolerance (IGT; n = 86), and newly diagnosed diabetes (NDD; n = 87) groups. Plasma Hhip levels were determined by an ELISA. The association between the Hhip and the presence of diabetes was examined by a multivariate linear regression analysis. Results: There were significant differences in the body mass index, systolic and diastolic blood pressure, fasting plasma glucose (FPG), post-load 2-h glucose, hemoglobin A1c (A1C), C-reactive protein, total cholesterol, triglyceride, and high- and low-density lipoprotein cholesterol levels among the groups. Concentrations of the Hhip were 2.45 ± 2.12, 4.40 ± 3.22, 4.44 ± 3.64, and 6.31 ± 5.35 ng/mL in subjects in the NGT, IFG, IGT, and NDD groups, respectively. In addition, we found that A1C and FPG were independently associated with Hhip concentrations. Using NGT as a reference group, IFG, IGT, and NDD were all independently associated with Hhip concentrations. Conclusions: Hhip was positively associated with prediabetes and type 2 diabetes mellitus.

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Kobune, Masayoshi, Hiroto Horiguchi, Shohei Kikuchi, Satoshi Iyama, Kohichi Takada, Kazuyuki Murase, Kaoru Ono, et al. "Stromal Cells Expressing Hedgehog-Interacting Protein Are One of the Main Regulators of the Hedgehog Signaling System in Myeloid Neoplasms." Blood 120, no. 21 (November 16, 2012): 3840. http://dx.doi.org/10.1182/blood.v120.21.3840.3840.

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Abstract Abstract 3840 Aberrant reactivation of Hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasm is unclear. In this study we assessed the expression of Hh-related proteins in normal human CD34+ cells, CD34+ leukemic/dysplastic cells and BM stromal cells. Both Indian hedgehog (Ihh) and its signal transducer, SMO, were expressed in CD34+ acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) derived cells, suggesting that Ihh could be affected in an autocrine manner. Remarkably, expression of the endogenous Hh signaling inhibitor, human hedgehog-interacting protein (HHIP), in AML/MDS-associated stromal cells was significantly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression level in BM stromal cells highly correlated with their tumor-supporting activity of SMO+ leukemic cells. Demethylating agent 5-aza-dC rescued HHIP expression via demethylation of HHIP gene and reduced the leukemia-supporting activity of AML/MDS-associated stromal cells. This effect of 5-aza-dC was negated by HHIP shRNA transfer into stromal cells. These results indicate that suppression of stromal HHIP expression could be involved in the progression of AML/MDS and 5-aza-dC may improve the protective function of BM stromal cells for AML/MDS. Disclosures: No relevant conflicts of interest to declare.

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Ortega-Martínez, Alejandro, Gloria Pérez-Rubio, Alejandra Ramírez-Venegas, María Elena Ramírez-Díaz, Filiberto Cruz-Vicente, María de Lourdes Martínez-Gómez, Espiridión Ramos-Martínez, Edgar Abarca-Rojano, and Ramcés Falfán-Valencia. "Participation of HHIP Gene Variants in COPD Susceptibility, Lung Function, and Serum and Sputum Protein Levels in Women Exposed to Biomass-Burning Smoke." Diagnostics 10, no. 10 (September 23, 2020): 734. http://dx.doi.org/10.3390/diagnostics10100734.

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Background: A variety of organic materials (biomass) are burned for cooking and heating purposes in poorly ventilated houses; smoke from biomass combustion is considered an environmental risk factor for chronic obstructive pulmonary disease COPD. In this study, we attempted to determine the participation of single-nucleotide variants in the HHIP (hedgehog-interacting protein) gene in lung function, HHIP serum levels, and HHIP sputum supernatant levels in Mexican women with and without COPD who were exposed to biomass-burning smoke. Methods: In a case-control study (COPD-BS, n = 186, BBES, n = 557) in Mexican women, three SNPs (rs13147758, rs1828591, and rs13118928) in the HHIP gene were analyzed by qPCR; serum and supernatant sputum protein levels were determined through ELISA. Results: The rs13118928 GG genotype is associated with decreased risk (p = 0.021, OR = 0.51, CI95% = 0.27–0.97) and the recessive genetic model (p = 0.0023); the rs1828591-rs13118928 GG haplotype is also associated with decreased risk (p = 0.04, OR = 0.65, CI95% 0.43–0.98). By the dominant model (rs13118928), the subjects with one or two copies of the minor allele (G) exhibited higher protein levels. Additionally, two correlations with the AG genotype were identified: BBES with FEV1 (p = 0.03, r2 = 0.53) and COPD-BS with FEV1/FVC (p = 0.012, r2 = 0.54). Conclusions: Single-nucleotide variants in the HHIP gene are associated with decreased COPD risk, higher HHIP serum levels, and better lung function in Mexican women exposed to biomass burning.

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Nie, Di-min, Qiu-ling Wu, Peng Zheng, Ping Chen, Ran Zhang, Bei-bei Li, Jun Fang, Ling-hui Xia, and Mei Hong. "Endothelial microparticles carrying hedgehog-interacting protein induce continuous endothelial damage in the pathogenesis of acute graft-versus-host disease." American Journal of Physiology-Cell Physiology 310, no. 10 (May 15, 2016): C821—C835. http://dx.doi.org/10.1152/ajpcell.00372.2015.

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Accumulating evidence suggests that endothelial microparticles (EMPs), a marker of endothelial damage, are elevated in acute graft-versus-host disease (aGVHD), and that endothelial damage is implicated in the pathogenesis of aGVHD, but the mechanisms remain elusive. In this study, we detected the plasma EMP levels and endothelial damage in patients and mice with aGVHD in vivo and then examined the effects of EMPs derived from injured endothelial cells (ECs) on endothelial damage and the role of hedgehog-interacting protein (HHIP) carried by EMPs in these effects in vitro. Our results showed that EMPs were persistently increased in the early posttransplantation phase in patients and mice with aGVHD. Meanwhile, endothelial damage was continuous in aGVHD mice, but was temporary in non-aGVHD mice after transplantation. In vitro, EMPs induced endothelial damage, including increased EC apoptosis, enhanced reactive oxygen species, decreased nitric oxide production and impaired angiogenic activity. Enhanced expression of HHIP, an antagonist for the Sonic hedgehog (SHH) signaling pathway, was observed in patients and mice with aGVHD and EMPs from injured ECs. The endothelial damage induced by EMPs was reversed when the HHIP incorporated into EMPs was silenced with an HHIP small interfering RNA or inhibited with the SHH pathway agonist, Smoothened agonist. This work supports a feasible vicious cycle in which EMPs generated during endothelial injury, in turn, aggravate endothelial damage by carrying HHIP into target ECs, contributing to the continuously deteriorating endothelial damage in the development of aGVHD. EMPs harboring HHIP would represent a potential therapeutic target for aGVHD.

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Doyard, M., N. Fatih, A. Monnier, M. L. Island, M. Aubry, P. Leroyer, R. Bouvet, et al. "Iron excess limits HHIPL-2 gene expression and decreases osteoblastic activity in human MG-63 cells." Osteoporosis International 23, no. 10 (January 12, 2012): 2435–45. http://dx.doi.org/10.1007/s00198-011-1871-z.

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Zhang, Zili, Jian Wang, Zeguang Zheng, Xindong Chen, Xiansheng Zeng, Yi Zhang, Defu Li, et al. "Genetic Variants in the Hedgehog Interacting Protein Gene Are Associated with the FEV1/FVC Ratio in Southern Han Chinese Subjects with Chronic Obstructive Pulmonary Disease." BioMed Research International 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/2756726.

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Background. Convincing evidences have demonstrated the associations between HHIP and FAM13a polymorphisms and COPD in non-Asian populations. Here genetic variants in HHIP and FAM13a were investigated in Southern Han Chinese COPD. Methods. A case-control study was conducted, including 989 cases and 999 controls. The associations between SNPs genotypes and COPD were performed by a logistic regression model; for SNPs and COPD-related phenotypes such as lung function, COPD severity, pack-year of smoking, and smoking status, a linear regression model was employed. Effects of risk alleles, genotypes, and haplotypes of the 3 significant SNPs in the HHIP gene on FEV1/FVC were also assessed in a linear regression model in COPD. Results. The mean FEV1/FVC% value was 46.8 in combined COPD population. None of the 8 selected SNPs apparently related to COPD susceptibility. However, three SNPs (rs12509311, rs13118928, and rs182859) in HHIP were associated significantly with the FEV1/FVC% (Pmax = 4.1 × 10−4) in COPD adjusting for gender, age, and smoking pack-years. Moreover, statistical significance between risk alleles and the FEV1/FVC% (P = 2.3 × 10−4), risk genotypes, and the FEV1/FVC% (P = 3.5 × 10−4) was also observed in COPD. Conclusions. Genetic variants in HHIP were related with FEV1/FVC in COPD. Significant relationships between risk alleles and risk genotypes and FEV1/FVC in COPD were also identified.

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Jiang, Xuejie, Dan Xu, Fang Chen, Ling Jiang, Guopan Yu, Fanyi Meng, Xiaoli Liu, and Qifa Liu. "BM-MSC Hhip Induced Microenvironment Protection from Chemotherapy in AML Via Ptch/Smo/Gli Pathwa." Blood 128, no. 22 (December 2, 2016): 5235. http://dx.doi.org/10.1182/blood.v128.22.5235.5235.

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Abstract Introduction. The mechanism of drug resistance is complicated in acute myeloid leukemia (AML), bone microenvironment provides protection niche for leukemia stem cells (LSC), and considered as an internal environment for AML cells to escape from chemotherapeutics cytotoxicity, but mechanism of drug resistance induced by microenvironment mesenchymal stem cell (MSC) isn't completely clear. In prophase study, it was found that Ptch/Smo/Glis pathway was the key in the network of AML drug resistance. Smo inhibition improved the survival of AML-bearing mice. Low expression of HHIP was found in refractory AML MSC and bone morrow liquid, overexpression of Smo and Gli-1 was verified in AML cells, and negatively correlated with prognosis in AML patients. Chemotherapeutic drug sensitivity was decreased in AML cells after co-cultured with AML MSC in vitro. Methods. Bone morrow samples from AML patients and normal donors were collected to culture MSC cells. HL60/ADM and Kasumi-1 cells as well as HL60、KG-1cells were treated with daunomycin (DNR) or cytosine arabinoside (Ara-C) when cocultured with MSC. Cell cycle and apoptosis were determined by flow cytometry. The expression of HHIP was determined by confocal image and western blotting. Smo and Gli-1 activity was determined by western blotting. Result. We took advantage of AML cells cocultured with MSC to imitate leukemic microenvironment in vitro. Co-culture with AML BM-MSC decreased the sensitivity to DNR or Ara-C compared with normal BM-MSC in HL60/ADM or Kasumi-1 cells. Flow cytometry analysis showed that cells in S phase and percentage of apoptosis cells were increased after co-culture with AML MSC. Western blotting also determined that low expression of HHIP was detected in refractory AML BM-MSC, Smo and Gli-1 expression were increased in HL60/ADM or Kasumi-1 cells after co-cultured with MSC. Confocal analysis also confirmed that the combination of HHIP and Ptch was decreased in AML MSC co-culture, Smo/Gli-1 pathway was activated through decreased inhibition of Shh in refractory AML cells co-cultured with MSC. Samples from AML patients also demonstrated that HHIP expression in AML BM-MSC was lower than that in normal BM-MSC, especially in refractory AML samples. HHIP expression in BM-MSC was negatively related to Smo and Gli-1 activity. Clinic data also showed that AML patients with overexpression of HHIP had a worse prognosis. Conclusion. Our study demonstrated expression of BM-MSC HHIP was negatively related to activity of Ptch/Smo/Glis in AML. Low expression of BM-MSC HHIP resulted in activating Ptch/Smo/Gli pathway, and indicated drug resisitance and bad prognosis in AML. This project is connected with basic research and clinic, and provides support for diagnosis and targeted therapy in AML. Disclosures No relevant conflicts of interest to declare.

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Lee, Woo, Seul Lee, Seung Yim, Daham Kim, Hyunji Kim, Seonhyang Jeong, Sang Jung, Young Jo, and Jandee Lee. "Whole Exome Sequencing Identifies a Novel Hedgehog-Interacting Protein G516R Mutation in Locally Advanced Papillary Thyroid Cancer." International Journal of Molecular Sciences 19, no. 10 (September 21, 2018): 2867. http://dx.doi.org/10.3390/ijms19102867.

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Locally advanced thyroid cancer exhibits aggressive clinical features requiring extensive neck dissection. Therefore, it is important to identify changes in the tumor biology before local progression. Here, whole exome sequencing (WES) using tissues from locally advanced papillary thyroid cancer (PTC) presented a large number of single nucleotide variants (SNVs) in the metastatic lymph node (MLN), but not in normal tissues and primary tumors. Among those MLN-specific SNVs, a novel HHIP G516R (G1546A) mutation was also observed. Interestingly, in-depth analysis for exome sequencing data from the primary tumor presented altered nucleotide ‘A’ at a very low frequency indicating intra-tumor heterogeneity between the primary tumor and MLN. Computational prediction models such as PROVEAN and Polyphen suggested that HHIP G516R might affect protein function and stability. In vitro, HHIP G516R increased cell proliferation and promoted cell migration in thyroid cancer cells. HHIP G516R, a missense mutation, could be a representative example for the intra-tumor heterogeneity of locally advanced thyroid cancer, which can be a potential future therapeutic target for this disease.

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Fawcett, Katherine A., Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, et al. "Variants associated with HHIP expression have sex-differential effects on lung function." Wellcome Open Research 5 (May 24, 2021): 111. http://dx.doi.org/10.12688/wellcomeopenres.15846.2.

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Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10-8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.

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Fawcett, Katherine A., Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, et al. "Variants associated with HHIP expression have sex-differential effects on lung function." Wellcome Open Research 5 (June 1, 2020): 111. http://dx.doi.org/10.12688/wellcomeopenres.15846.1.

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Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10-8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.

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Shah, Rachit, Alexander Strom, Andrew Zhou, Kimberly M. Maize, Barry C. Finzel, and Carston R. Wagner. "Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1." ACS Medicinal Chemistry Letters 7, no. 8 (June 15, 2016): 780–84. http://dx.doi.org/10.1021/acsmedchemlett.6b00169.

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Holtz, A. M., K. A. Peterson, Y. Nishi, S. Morin, J. Y. Song, F. Charron, A. P. McMahon, and B. L. Allen. "Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning." Development 140, no. 16 (July 30, 2013): 3423–34. http://dx.doi.org/10.1242/dev.095083.

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Bo, Changwen, Xiuli Li, Li He, Sujing Zhang, Na Li, and Yonghui An. "A novel long noncoding RNA HHIP-AS1 suppresses hepatocellular carcinoma progression through stabilizing HHIP mRNA." Biochemical and Biophysical Research Communications 520, no. 2 (December 2019): 333–40. http://dx.doi.org/10.1016/j.bbrc.2019.09.137.

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Rodríguez-Pérez, José Manuel, Rosalinda Posadas-Sánchez, Ruben Blachman-Braun, Gilberto Vargas-Alarcón, Carlos Posadas-Romero, Adrián Asael Rodríguez-Cortés, Fabiola López-Bautista, et al. "HHIPL-1 (rs2895811) gene polymorphism is associated with cardiovascular risk factors and cardiometabolic parameters in Mexicans patients with myocardial infarction." Gene 663 (July 2018): 34–40. http://dx.doi.org/10.1016/j.gene.2018.04.030.

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Ahmed, Mohamed, Peter Schwendt, Michal Siv�, and Jarom�n Marek. "Synthesis and characterization of vanadium(V) complexes with ?-hydroxyhippuric acid. The X-ray crystal structure of (NBu 4)2[V2O2(O2)2(R-?-hhip) (S-?-hhip)]�5H2O,[?-hhip = ?-hydroxyhippurato(2-)]." Transition Metal Chemistry 29, no. 6 (September 2004): 675–80. http://dx.doi.org/10.1007/s11243-004-5363-2.

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32

Ibeagha-Awemu, Eveline, Ran Li, Pier-Luc Dudemaine, Duy Do, and Nathalie Bissonnette. "Transcriptome Analysis of Long Non-Coding RNA in the Bovine Mammary Gland Following Dietary Supplementation with Linseed Oil and Safflower Oil." International Journal of Molecular Sciences 19, no. 11 (November 15, 2018): 3610. http://dx.doi.org/10.3390/ijms19113610.

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This study aimed to characterize the long non-coding RNA (lncRNA) expression in the bovine mammary gland and to infer their functions in dietary response to 5% linseed oil (LSO) or 5% safflower oil (SFO). Twelve cows (six per treatment) in mid lactation were fed a control diet for 28 days followed by a treatment period (control diet supplemented with 5% LSO or 5% SFO) of 28 days. Mammary gland biopsies were collected from each animal on day-14 (D-14, control period), D+7 (early treatment period) and D+28 (late treatment period) and were subjected to RNA-Sequencing and subsequent bioinformatics analyses. Functional enrichment of lncRNA was performed via potential cis regulated target genes located within 50 kb flanking regions of lncRNAs and having expression correlation of >0.7 with mRNAs. A total of 4955 lncRNAs (325 known and 4630 novel) were identified which potentially cis targeted 59 and 494 genes in LSO and SFO treatments, respectively. Enrichments of cis target genes of lncRNAs indicated potential roles of lncRNAs in immune function, nucleic acid metabolism and cell membrane organization processes as well as involvement in Notch, cAMP and TGF-β signaling pathways. Thirty-two and 21 lncRNAs were differentially expressed (DE) in LSO and SFO treatments, respectively. Six genes (KCNF1, STARD13, BCL6, NXPE2, HHIPL2 and MMD) were identified as potential cis target genes of six DE lncRNAs. In conclusion, this study has identified lncRNAs with potential roles in mammary gland functions and potential candidate genes and pathways via which lncRNAs might function in response to LSO and SFA.

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Jeong, J. "Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1." Development 132, no. 1 (December 2, 2004): 143–54. http://dx.doi.org/10.1242/dev.01566.

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34

Schneider, Paulo Renato, César Augusto Guimarães Finger, Juarez Martins Hoppe, Ronaldo Drescher, Luciano W. Scheeren, Gerson Luis Mainardi, and Frederico Dimas Fleig. "Produção de Eucalyptus grandis Hhill ex Maiden em diferentes intensidades de desbaste." Ciência Florestal 8, no. 1 (March 30, 1998): 129. http://dx.doi.org/10.5902/19805098357.

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O efeito de diferentes intensidades de desbaste sobre a produção Eucalyptus grandis Hill ex Maiden implantado no ano de 1981, em espaçamento inicial de 3,0 x 2,0 metros, na região de Cachoeira do Sul, Rio Grande do Sul, foi estudado com delineamento de blocos ao acaso, com duas repetições e quatro tratamentos: testemunha, sem desbastes, manutenção de 40%, 50% e 60% da área basal da testemunha, constando-se diferença significativa entre os tratamentos, ao nível de 5% de probabilidade. A produção máxima (756,3 m3cc/ha) foi obtida na testemunha, sem desbaste, que não diferiu estatísticamente de 639,6 m3cc/ha, obtido no tratamento com manutenção de 60% da área basal da testemunha, porém diferiu dos tratamentos com manutenção de 50% e 40% da área basal da testemunha. A redução da área basal incrementou a concentração das freqüências nas maiores classes de diâmetro, deslocando a distribuição para a direita, porém com perdas expressivas de produção total e acréscimo significativo no diâmetro. A manutenção de 60% da área basal da testemunha permitiu as menores perdas de produção, cerca de 15,4%, e um ganho de 6,4cm ou 23,9% em incremento diamétrico das árvores remanescentes quando comparado com a testemunha, sem desbaste.

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Agrawal, Vijayendra, Dong Young Kim, and Young-Guen Kwon. "Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis." Experimental & Molecular Medicine 49, no. 1 (January 2017): e289-e289. http://dx.doi.org/10.1038/emm.2016.139.

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SUBRAMANIAN, ABHISHEK, and RAM RUP SARKAR. "DYNAMICS OF GLI REGULATION AND A STRATEGY TO CONTROL CANCEROUS SITUATION: HEDGEHOG SIGNALING PATHWAY REVISITED." Journal of Biological Systems 23, no. 04 (November 30, 2015): 1550033. http://dx.doi.org/10.1142/s0218339015500333.

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The hedgehog signaling cascade generates highly diverse, fine-tuned responses in response to the external stimulus by the sonic hedgehog (SHH) protein. This is required for the flawless functioning of the cell, its development, survival and proliferation; maintained through production of Glioma protein (GLI) and transcriptional activation of its target genes. Any change in the behavior of GLI response by ectopic expression of SHH or mutations in the core pathway components may cause serious consequences in the cell fate through rapid, uncontrolled and elevated production of GLI. Here, we present a simple but extensive computational model that considers the detailed reaction mechanisms involved in the hedgehog signal transduction and provides a detailed insight into regulation of GLI. For the first time, by explicit involvement of suppressor of fused (SUFU) and Hedgehog interacting protein (HHIP) reaction kinetics in the model, we try to demonstrate the vital importance of HHIP and SUFU in maintaining the graded response of GLI in response to SHH. By performing parameter variations, we capture the conversion of a graded response of GLI to an ultrasensitive switch under SUFU-deficient conditions that might predispose abnormal embryonic development and the irreversible switching response of GLI that corresponds to signal-independent pathway activation observed in cancers.

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SONG, YU, and YUN ZUO. "Occurrence of HHIP gene CpG island methylation in gastric cancer." Oncology Letters 8, no. 5 (September 10, 2014): 2340–44. http://dx.doi.org/10.3892/ol.2014.2518.

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Chang, Liang, Ping Zhang, Dan Zhao, Huibin Liu, Qiushi Wang, Chenlong Li, Wenzhong Du, et al. "The hedgehog antagonist HHIP as a favorable prognosticator in glioblastoma." Tumor Biology 37, no. 3 (October 19, 2015): 3979–86. http://dx.doi.org/10.1007/s13277-015-3442-y.

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Maize, Kimberly M., Rachit Shah, Alex Strom, Sidath Kumarapperuma, Andrew Zhou, Carston R. Wagner, and Barry C. Finzel. "A Crystal Structure Based Guide to the Design of Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) Activated ProTides." Molecular Pharmaceutics 14, no. 11 (October 26, 2017): 3987–97. http://dx.doi.org/10.1021/acs.molpharmaceut.7b00664.

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Chang, Liang, Lisheng Yin, Dongzhi Zhang, Chao Wang, Guofu Li, Chunlei Tan, Xuexin Zhang, and Jun Su. "MicroRNA-221 promotes tumor progression by targeting HHIP in human glioblastoma." Translational Cancer Research 10, no. 2 (February 2021): 1073–81. http://dx.doi.org/10.21037/tcr-21-99.

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Braster, Rens, Marijn Bögels, Hreinn Benonisson, Manfred Wuhrer, Rosina Plomp, Arthur E. H. Bentlage, Rianne Korthouwer, et al. "Afucosylated IgG Targets FcγRIV for Enhanced Tumor Therapy in Mice." Cancers 13, no. 10 (May 14, 2021): 2372. http://dx.doi.org/10.3390/cancers13102372.

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Promising strategies for maximizing IgG effector functions rely on the introduction of natural and non-immunogenic modifications. The Fc domain of IgG antibodies contains an N-linked oligosaccharide at position 297. Human IgG antibodies lacking the core fucose in this glycan have enhanced binding to human (FcγR) IIIa/b, resulting in enhanced antibody dependent cell cytotoxicity and phagocytosis through these receptors. However, it is not yet clear if glycan-enhancing modifications of human IgG translate into more effective treatment in mouse models. We generated humanized hIgG1-TA99 antibodies with and without core-fucose. C57Bl/6 mice that were injected intraperitoneally with B16F10-gp75 mouse melanoma developed significantly less metastasis outgrowth after treatment with afucosylated hIgG1-TA99 compared to mice treated with wildtype hhIgG1-TA99. Afucosylated human IgG1 showed stronger interaction with the murine FcγRIV, the mouse orthologue of human FcγRIIIa, indicating that this glycan change is functionally conserved between the species. In agreement with this, no significant differences were observed in tumor outgrowth in FcγRIV-/- mice treated with human hIgG1-TA99 with or without the core fucose. These results confirm the potential of using afucosylated therapeutic IgG to increase their efficacy. Moreover, we show that afucosylated human IgG1 antibodies act across species, supporting that mouse models can be suitable to test afucosylated antibodies.

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Glotov, Andrey S., Elena S. Vashukova, Oleg S. Glotov, Roman V. Kurilov, Irina V. Tarkovskaia, Ekaterina Y. Ditkina, Irina V. Pugacheva, et al. "A study of genetic markers of human height." Ecological genetics 10, no. 4 (December 15, 2012): 77–84. http://dx.doi.org/10.17816/ecogen10477-84.

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A population study of polymorphisms of EFEMP1, ZBTB38, HHIP, LCORL, ADAMTSL3, CDH13, JAZF1, IGF1R, GHSR, CABLES1, IFNG, VDR3, and IGFBP3 genes, which possibly influence human height, was carried out using PCR-RFLP. Population frequencies of alleles and genotypes for these genes were established. A correlation between the rs572169 variant of GSHR gene and male height was found . We suggest a model for prediction of human height on the basis of logistic regression method. The obtained data indicate a possibility to assess human height on the basis of genetic markers.

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Shah, Rachit, Tsui-Fen Chou, Kimberly M. Maize, Alexander Strom, Barry C. Finzel, and Carston R. Wagner. "Inhibition by divalent metal ions of human histidine triad nucleotide binding protein1 (hHint1), a regulator of opioid analgesia and neuropathic pain." Biochemical and Biophysical Research Communications 491, no. 3 (September 2017): 760–66. http://dx.doi.org/10.1016/j.bbrc.2017.07.111.

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Safgren, Stephanie L., Rachel L. O. Olson, Anne M. Vrabel, Luciana L. Almada, David L. Marks, Nelmary Hernandez-Alvarado, Alexandre Gaspar-Maia, and Martin E. Fernandez-Zapico. "The transcription factor GLI1 cooperates with the chromatin remodeler SMARCA2 to regulate chromatin accessibility at distal DNA regulatory elements." Journal of Biological Chemistry 295, no. 26 (May 6, 2020): 8725–35. http://dx.doi.org/10.1074/jbc.ra120.013268.

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The transcription factor GLI1 (GLI family zinc finger 1) plays a key role in the development and progression of multiple malignancies. To date, regulation of transcriptional activity at target gene promoters is the only molecular event known to underlie the oncogenic function of GLI1. Here, we provide evidence that GLI1 controls chromatin accessibility at distal regulatory regions by modulating the recruitment of SMARCA2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2) to these elements. We demonstrate that SMARCA2 endogenously interacts with GLI1 and enhances its transcriptional activity. Mapping experiments indicated that the C-terminal transcriptional activation domain of GLI1 and SMARCA2's central domains, including its ATPase motif, are required for this interaction. Interestingly, similar to SMARCA2, GLI1 overexpression increased chromatin accessibility, as indicated by results of the micrococcal nuclease assay. Further, results of assays for transposase-accessible chromatin with sequencing (ATAC-seq) after GLI1 knockdown supported these findings, revealing that GLI1 regulates chromatin accessibility at several regions distal to gene promoters. Integrated RNA-seq and ATAC-seq data analyses identified a subset of differentially expressed genes located in cis to these regulated chromatin sites. Finally, using the GLI1-regulated gene HHIP (Hedgehog-interacting protein) as a model, we demonstrate that GLI1 and SMARCA2 co-occupy a distal chromatin peak and that SMARCA2 recruitment to this HHIP putative enhancer requires intact GLI1. These findings provide insights into how GLI1 controls gene expression in cancer cells and may inform approaches targeting this oncogenic transcription factor to manage malignancies.

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Zhou, Xiaobo, Rebecca M. Baron, Megan Hardin, Michael H. Cho, Jan Zielinski, Iwona Hawrylkiewicz, Pawel Sliwinski, et al. "Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP." Human Molecular Genetics 21, no. 6 (December 2, 2011): 1325–35. http://dx.doi.org/10.1093/hmg/ddr569.

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46

Collins, Samuel A., Jane S. A. Lucas, Hazel M. Inskip, Keith M. Godfrey, Graham Roberts, and John W. Holloway. "HHIP,HDAC4,NCR3andRARBpolymorphisms affect fetal, childhood and adult lung function: Table 1–." European Respiratory Journal 41, no. 3 (February 28, 2013): 756–57. http://dx.doi.org/10.1183/09031936.00171712.

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47

Shah, Rachit, Kimberly M. Maize, Xin Zhou, Barry C. Finzel, and Carston R. Wagner. "Caught before Released: Structural Mapping of the Reaction Trajectory for the Sofosbuvir Activating Enzyme, Human Histidine Triad Nucleotide Binding Protein 1 (hHint1)." Biochemistry 56, no. 28 (July 10, 2017): 3559–70. http://dx.doi.org/10.1021/acs.biochem.7b00148.

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Kozirovskis, Viktors, Elīna Zandberga, Melita Magone, Gunta Purkalne, Aija Linē, and Uldis Vikmanis. "Expression of the Sonic Hedgehog Embryonic Signalling Pathway Components in Matched Pre-Treatment and Relapsed Small Cell Lung Cancer Biopsies." Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences. 75, no. 5 (October 1, 2021): 335–42. http://dx.doi.org/10.2478/prolas-2021-0049.

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Abstract Cancer stem cells may be responsible for tumour regrowth and acquisition of resistance in small cell lung cancer (SCLC). The Hedgehog pathway regulates survival and proliferation of tissue progenitor and stem cell populations, promoting the expression of stem cell related and proliferative genes. We evaluated the Sonic Hedgehog (Shh) embryonic signalling pathway in relapsed SCLC. Expression levels of Shh related genes GLI1, SMO, SUFU, PTCH1, HHIP, BCL2, BMI, ZEB1, ZEB2, N-MYC, Twist1 were analysed by qRT-PCR in matched pre-treatment and relapsed tumour fresh frozen biopsies of three SCLC patients. Expression of each gene was compared using the paired samples t-test, as well as comparison of mean expression levels was done. Data were statistically interpreted using the MedCalc version 10.2.0.0 software. 2.9-fold lower mean mRNA expression of the major Hedgehog activation indicator GLI1 was observed in relapsed samples (p = 0.0529). Mean expression of six Shh inducible genes, PTCH1, HHIP, N-MYC, ZEB2, Twist1, ZEB1, was also downregulated by 2.6-, 2.2-, 1.9-, 1.8-, 1.2-, 1.1-fold, respectively (p = 0.4252, p = 0.1268, p = 0.2480, p = 0.1169, p = 0.1480, p = 0.7595, respectively). 1.8-fold mean expression decrease was found for Gli activator Smo (p = 0.4111). Only the Shh pathway inhibitor SUFU and two other examined Hedgehog signalling inducible genes BCL2 and BMI in relapsed SCLC showed 0.8-, 0.9-,and 0.8-fold increase of expression, respectively (p = 0.3074, p = 0.7921, and p = 0.3822, respectively). To our knowledge, this is the first report of comparison of Shh signalling in matched pre-treatment and relapsed SCLC biopsies. Our data show decreased activity for majority of Shh pathway components in relapsed SCLC, although difference did not reach statistical significance.

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Martin, S. T., N. Sato, S. Dhara, R. Chang, Steven R. Hustinx, T. Abe, Anirban Maitra, and Michael Goggins. "Aberrant methylation of the human hedgehog interacting protein (HHIP) gene in pancreatic neoplasms." Cancer Biology & Therapy 4, no. 7 (July 2005): 728–33. http://dx.doi.org/10.4161/cbt.4.7.1802.

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Lahmar, M. Z., E. Ahmed, I. Vachier, A. Fort, G. Marin, N. Molinari, A. Bergougnoux, and A. Bourdin. "Hedgehog Interacting Protein (HHIP) polymorphisms involved in early chronic obstructive pulmonary disease (COPD)." Revue des Maladies Respiratoires 39, no. 2 (February 2022): 115. http://dx.doi.org/10.1016/j.rmr.2022.02.017.

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