Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling

Griffiths, Samuel C.; Schwab, Rebekka A.; Omari, Kamel El; Bishop, B.; Iverson, Ellen J.; Malinauskas, Tomas; Dubey, Ramin; Mei, Qian; Covey, Douglas F.; Gilbert, Robert J.C.; Rohatgi, Rajat; Siebold, Christian

doi:10.1038/s41467-021-27475-2

Cited by 21 publications

(16 citation statements)

References 100 publications

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“…1e ), PTCH1 staining was generally enriched in cells between the GC basement membrane and the sTC layer. PTCH1 is both a receptor that activates Hh signaling, as well as a target of pathway activation 28 ; HHIP acts as a decoy receptor for Hh ligands, thereby having an inhibitory effect on activation 29 . Accordingly, PTCH1 and GLI1, both effectors of Hh signaling, were reduced in THBD + cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Human theca arises from ovarian stroma and is comprised of three discrete subtypes

et al. 2023

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Theca cells serve multiple essential functions during the growth and maturation of ovarian follicles, providing structural, metabolic, and steroidogenic support. While the function of theca during folliculogenesis is well established, their cellular origins and the differentiation hierarchy that generates distinct theca sub-types, remain unknown. Here, we performed single cell multi-omics analysis of primary cell populations purified from human antral stage follicles (1–3 mm) to define the differentiation trajectory of theca/stroma cells. We then corroborated the temporal emergence and growth kinetics of defined theca/stroma subpopulations using human ovarian tissue samples and xenografts of cryopreserved/thawed ovarian cortex, respectively. We identified three lineage specific derivatives termed structural, androgenic, and perifollicular theca cells, as well as their putative lineage-negative progenitor. These findings provide a framework for understanding the differentiation process that occurs in each primordial follicle and identifies specific cellular/molecular phenotypes that may be relevant to either diagnosis or treatment of ovarian pathologies.

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Section: Resultsmentioning

confidence: 99%

Human theca arises from ovarian stroma and is comprised of three discrete subtypes

et al. 2023

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“…Hedgehog interacting protein (HHIP) is a key regulator of fundamental processes in embryonic development and an endogenous antagonist of the Hedgehog signaling pathway 34,35 . Increasing studies evidenced that aberrant activation of the Hedgehog signaling pathway is one of the main causes of cancer progression, 36,37 especially serving as is a negative regulator of Hedgehog signaling pathway 35 .…”

Section: Discussionmentioning

confidence: 99%

CircFAM114A2 inhibits the progression of hepatocellular carcinoma via miR‐630/HHIP axis

Lai

Liu

et al. 2023

Cancer Medicine

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Background Many studies have shown that circular RNAs (circRNAs) are abnormally expressed in various tumor tissues and served as a key regulator in the occurrence and development of cancer. However, in hepatocellular carcinoma (HCC), the molecular mechanism of circRNAs in body fluids remains to be further explored. Methods The expression levels of genes and proteins were detected by quantitative real‐time polymerase chain reaction (qRT‐PCR) and western blotting, respectively. Cell counting Kit‐8 (CCK‐8), 5‐Ethynyl‐2'‐deoxyuridine (EdU), wound healing assay, Transwell assays, flow cytometry, and tumor formation models in nude mice were conducted to investigate the effects of circFAM114A2 on HCC cells both in vitro and in vivo. RNA antisense purification (RAP), dual luciferase reporter assays and rescue assays were carried out to verify the interaction between circFAM114A2, miR‐630 and HHIP. Results CircFAM114A2 was significantly downregulated in HCC tissues and was associated with microvascular invasion and lymph node metastasis of HCC patients. We also observed that circFAM114A2 was lowly expressed in HCC plasma, which may serve as an effective biomarker to screen HCC patients from healthy controls (area under curve (AUC)=0.922). In vitro, circFAM114A2 overexpression significantly blunted HCC cell proliferation, migration, invasion, and promoted apoptosis, whereas circFAM114A2 silencing posed opposite effects. In vivo, circFAM114A2 overexpression inhibited the growth of HCC cells. Mechanistically, circFAM114A2 could increase the expression of the tumor suppressor HHIP via acting as a sponge for miR‐630. Conclusions CircFAM114A2 exerts a tumor suppressor role in HCC through miR‐630/HHIP axis, and may be served as a potential diagnostic and therapeutic biomarker for HCC patients.

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“…When the HH signaling pathway is over-activated, the up-regulation of HHIP inhibits the activity of Hedgehog signaling pathway and results in a negative feedback regulation. HHIP binds with SHH in cell membrane and blocks the activation of the Hedgehog signaling pathway [ 37 ]. In the present study, we found that the downstream molecules of Hedgehog signaling pathway, Gli1 and Gli2, were down-regulated after the overexpression of lncRNA HHIP-AS1, which suppressed the osteogenic differentiation of BM-MSCs.…”

Section: Discussionmentioning

confidence: 99%

lncRNA HHIP-AS1/HHIP modulates osteogenic differentiation of BM-MSCs by regulating Hedgehog signaling pathway

Yin

Wang²,

Liu

et al. 2022

Aging

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Background: lncRNA, a type of non-coding RNA, plays an important role in the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs). In this study, lncRNA and mRNA microarrays were performed to study the change of gene expression during osteogenic differentiation of BM-MSCs. We focused on Hedgehog interacting protein (HHIP), because HHIP mRNA and lncRNA HHIP-AS1 were gradually down-regulated on days 0, 7, and 14 during osteogenic differentiation. In addition, the gene coding lncRNA HHIP-AS1 is located on the anti-sense of Hhip gene, implying the potential interaction between lncRNA HHIP-AS1 and HHIP mRNA. Methods: BM-MSCs with over-expressed or silenced lncRNA HHIP-AS1 were constructed to explore the biological role of HHIP-AS1 in osteogenic differentiation. BM-MSCs were lysed to determine the alkaline phosphatase activity. Fluorescence in situ hybridization and immunofluorescence were performed to analyze HHIP-AS1, HHIP, RUNX2 and osteocalcin. Results: Overexpression of lncRNA HHIP-AS1 increased HHIP expression, which suppressed Hedgehog signaling pathway, as indicated by the reduction of SMO, Gli1 and Gli2. The suppression of Hedgehog signal was associated with the inhibited osteogenesis. HHIP knockdown abolished the suppression of osteogenesis induced by lncRNA HHIP-AS1 overexpression. Through binding to HHIP mRNA, lncRNA HHIP-AS1 recruited ELAVL1 to HHIP mRNA, whereby increasing the mRNA stability and the protein level. Conclusions: This study revealed that down-regulation of HHIP due to lncRNA HHIP-AS1 reduction promoted the osteogenic differentiation of BM-MSCs though removing the suppression of Hedgehog signal.

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Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling

Cited by 21 publications

References 100 publications

Human theca arises from ovarian stroma and is comprised of three discrete subtypes

Human theca arises from ovarian stroma and is comprised of three discrete subtypes

CircFAM114A2 inhibits the progression of hepatocellular carcinoma via miR‐630/HHIP axis

lncRNA HHIP-AS1/HHIP modulates osteogenic differentiation of BM-MSCs by regulating Hedgehog signaling pathway

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