Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hexavalent chromium [Cr(VI)] is a potent human lung carcinogen. Multiple mechanisms have been proposed that contribute to Cr(VI)-induced lung carcinogenesis including oxidative stress, DNA damage, genomic instability, and epigenetic modulation. However, the molecular mechanisms and pathways mediating Cr(VI) carcinogenicity have not been fully elucidated. Hedgehog (Hh) signaling is a key pathway that plays important roles in the formation of multiple tissues during embryogenesis and in the maintenance of stem cell populations in adults. Dysregulation of Hh signaling pathway has been reported in many human cancers. Here, we report a drastic reduction in both mRNA and protein levels of hedgehog-interacting protein (HHIP), a downstream target and a negative regulator of Hh signaling, in Cr(VI)-transformed cells. These findings point to a potential role of Hh signaling in Cr(VI)-induced malignant transformation and lung carcinogenesis. Cr(VI)-transformed cells exhibited DNA hypermethylation and silencing histone marks in the promoter region of HHIP, indicating that an epigenetic mechanism mediates Cr(VI)-induced silencing of HHIP. In addition, the major targets of Hh signaling (GLI1-3 and PTCH1) were significantly increased in Cr(VI)-transformed cells, suggesting an aberrant activation of Hh signaling in these cells. Moreover, ectopically expressing HHIP not only suppressed Hh signaling but also inhibited cell proliferation and anchorage-independent growth in Cr(VI)-transformed cells. In conclusion, these findings establish a novel regulatory mechanism underlying Cr(VI)-induced lung carcinogenesis, and provide new insights for developing a better diagnostic and prognostic strategy for Cr(VI)-related human lung cancer.
Carcinogenesis 2020 Jul 25
PMID:Downregulation of hedgehog-interacting protein (HHIP) contributes to hexavalent chromium-induced malignant transformation of human bronchial epithelial cells. 3271 Jun 11

The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.
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PMID:GLI1/GLI2 functional interplay is required to control Hedgehog/GLI targets gene expression. 3276 32

Basal cell carcinoma (BCC) is the most common malignant skin tumor. BCC displays a different behavior compared with other neoplasms, has a slow evolution, and metastasizes very rarely, but sometimes it causes an important local destruction. Chronic ultraviolet exposure along with genetic factors are the most important risk factors involved in BCC development. Mutations in the PTCH1 gene are associated with Gorlin syndrome, an autosomal dominant disorder characterized by the occurrence of multiple BCCs, but are also the most frequent mutations observed in sporadic BCCs. PTCH1 encodes for PTCH1 protein, the most important negative regulator of the Hedgehog (Hh) pathway. There are numerous studies confirming Hh pathway involvement in BCC pathogenesis. Although Hh pathway has been intensively investigated, it remains incompletely elucidated. Recent studies on BCC tumorigenesis have shown that in addition to Hh pathway, there are other signaling pathways involved in BCC development. In this review, we present recent advances in BCC carcinogenesis.
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PMID:Recent Advances in Signaling Pathways Comprehension as Carcinogenesis Triggers in Basal Cell Carcinoma. 3296 89


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