Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicates<i>SEC63</i>as potential target gene in hepatocarcinogenesis

Casper, Markus; Weber, Susanne N.; Kloor, Matthias; Müllenbach, Roman; Grobholz, Rainer; Lammert, Frank; Zimmer, Vincent

doi:10.3109/00365521.2012.752030

Cited by 20 publications

(18 citation statements)

References 41 publications

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“…DNA MMR genes play an important role in maintaining the integrity and stability of the genetic information and avoiding the occurrence of genetic mutations, which is a function closely related to the development of tumors [15,16]. It has been reported that MMR defects can lead to the development of colon, pancreatic, stomach, esophageal, ovarian and prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Correlation between polymorphisms in DNA mismatch repair genes and the risk of primary hepatocellular carcinoma for the Han population in northern China

Liu

Zhang

Jia

et al. 2015

Scandinavian Journal of Gastroenterology

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Section: Discussionmentioning

confidence: 99%

Correlation between polymorphisms in DNA mismatch repair genes and the risk of primary hepatocellular carcinoma for the Han population in northern China

Liu

Zhang

Jia

et al. 2015

Scandinavian Journal of Gastroenterology

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“…For SEC63 , frameshift mutations caused by microsatellite instability were found in 37.5% of microsatellite-unstable gastric cancers, 82 48.8% of colorectal cancers, 82 56% of small-bowel cancer associated with hereditary non-polyposis colorectal cancer 83 and in one case of hepatocellular carcinoma associated with Lynch syndrome. 84 However, functional analyses to further uncover the role of Sec63 in human carcinogenesis were solely conducted by Casper et al , 84 who showed that a low hepatic expression of SEC63 correlated with a decreased apoptosis rate and an increased proliferative activity of hepatocytes in BXD mice. Altogether, these studies indicate a potential role of SEC63 as a tumor suppressor gene in the carcinogenesis of gastric cancer, colorectal cancer and hepatocellular cancer (HCC) without, however, providing a link of disrupted Sec63 function to tumor cell biology in these entities.…”

Section: Mutation and Overexpression Of Sec Genes mentioning

confidence: 99%

Let’s talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine

Linxweiler

Schick

Zimmermann

2017

Sig Transduct Target Ther

135

130

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The heterotrimeric Sec61 complex and the dimeric Sec62/Sec63 complex are located in the membrane of the human endoplasmic reticulum (ER) and play a central role in translocation of nascent and newly synthesized precursor polypeptides into the ER. This process involves targeting of the precursors to the membrane and opening of the polypeptide conducting Sec61 channel for translocation. Apart from this central role in the intracellular transport of polypeptides, several studies of the last decade uncovered additional functions of Sec proteins in intracellular signaling: Sec62 can induce ER-phagy in the process of recovery of cells from ER stress and the Sec61 channel can also act as a passive ER calcium leak channel. Furthermore, mutations, amplifications and an overexpression of the SEC genes were linked to various diseases including kidney and liver diseases, diabetes and human cancer. Studies of the last decade could not only elucidate the functional role of Sec proteins in the pathogenesis of these diseases, but also demonstrate a relevance of Sec62 as a prognostic and predictive biomarker in head and neck cancer, prostate and lung cancer including a basis for new therapeutic strategies. In this article, we review the current understanding of protein transport across the ER membrane as central function of Sec proteins and further focus on recent studies that gave first insights into the functional role and therapeutic relevance of Sec61, Sec62 and Sec63 in human diseases.

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“…These downstream targets of XBP1s transcription factor were not selected randomly; they have certain roles in the events pertaining to cellular differentiation. High SEC63 expression has been shown to have an involvement in apoptosis and reduced proliferation in hepatic tumors ; ERDJ4 has been shown to have a crucial role in B cell differentiation in the event of hematopoiesis . Besides, DNAJC3 levels are known to increase during plasma cells differentiation ; the expression of PDIA3 and DNAJC3 was shown to be upregulated during T‐helper cell differentiation and treatment with IRE1α's endoribonuclease activity specific inhibitor 4μ8c downregulated their expression via inhibiting XBP1 mRNA splicing .…”

Section: Resultsmentioning

confidence: 99%

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

et al. 2019

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Neuroblastoma is an embryonic malignancy that arises out of the neural crest cells of the sympathetic nervous system. It is the most common childhood tumor known for its spontaneous regression via the process of differentiation. The induction of differentiation using small molecules such as retinoic acid is one of the therapeutic strategies to treat the residual disease. In this study, we have reported the effect of kaempferol (KFL) in inducing differentiation of neuroblastoma cells in vitro. Treatment of neuroblastoma cells with KFL reduced the proliferation and enhanced apoptosis along with the induction of neuritogenesis. Analysis of the expression of neuron‐specific markers such as β‐III tubulin, neuron‐specific enolase, and N‐myc downregulated gene 1 revealed the process of differentiation accompanying KFL‐induced apoptosis. Further analysis to understand the molecular mechanism of action showed that the effect of KFL is mediated by the activation of the endoribonuclease activity of inositol‐requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum‐resident transmembrane protein. In silico docking analysis and biochemical assays using recombinant human IRE1α confirm the binding of KFL to the ATP‐binding site of IRE1α, which thereby activates IRE1α ribonuclease activity. Treatment of cells with the small molecule STF083010, which specifically targets and inhibits the endoribonuclease activity of IRE1α, showed reduced expression of neuron‐specific markers and curtailed neuritogenesis. The knockdown of IRE1α using plasmid‐based shRNA lentiviral particles also showed diminished changes in the morphology of the cells upon KFL treatment. Thus, our study suggests that KFL induces differentiation of neuroblastoma cells via the IRE1α ‐XBP1 pathway.

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Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicatesSEC63as potential target gene in hepatocarcinogenesis

Cited by 20 publications

References 41 publications

Correlation between polymorphisms in DNA mismatch repair genes and the risk of primary hepatocellular carcinoma for the Han population in northern China

Correlation between polymorphisms in DNA mismatch repair genes and the risk of primary hepatocellular carcinoma for the Han population in northern China

Let’s talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

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