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Oxytocin receptor genetic alterations in hepatocellular carcinoma.

ABSTRACT: Purpose:Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related deaths with a very poor prognosis. Consequently, there is an urgent need for better understanding the molecular mechanisms, novel prognostic biomarkers, and more effective treatment options. There is an emerging link between oxytocin (OXT), the oxytocin receptor (OXTR), and cancer. However, the role of OXT or the OXTR in HCC remains unknown. The research question of this study was: Are there genetic alterations in the oxytocin (OXT) and oxytocin receptor (OXTR) genes in hepatocellular carcinoma (HCC) patients and do these alterations impact overall survival and disease-free survival. Methods:In this retrospective study, we reviewed 360 individual HCC patient data from The Cancer Genome Atlas (TCGA) using cBioPortal accessed in April 2018. The data in The Cancer Genome Atlas are from various institutions in the United States. Results:We found that 3% (11 of 360) of cases showed genetic alterations in the OXTR gene. The median months survival was lower for HCC cases with genetic alterations in the OXTR gene as compared to cases without genetic alteration in this gene (33.0 versus 60.84, respectively. Additionally, the median months disease-free survival was lower in cases with genetic alterations in the OXTR gene as compared to cases without alterations (8.64 versus 21.55, respectively). Conclusions:OXTR is a promising prognostic biomarker for HCC, and OXTR antagonists could have a future role as therapeutic agents for a subset of HCC patients. Further study of the detailed molecular mechanisms of OXT and OXTR in HCC is warranted.

SUBMITTER: Harricharran T

PROVIDER: S-EPMC7449247 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Oxytocin receptor genetic alterations in hepatocellular carcinoma.

Harricharran Trisheena T Ogunwobi Olorunseun O OO

SN comprehensive clinical medicine 20190614 7

<h4>Purpose</h4>Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related deaths with a very poor prognosis. Consequently, there is an urgent need for better understanding the molecular mechanisms, novel prognostic biomarkers, and more effective treatment options. There is an emerging link between oxytocin (OXT), the oxytocin receptor (OXTR), and cancer. However, the role of OXT or the OXTR in HCC remains unknown. The research question of this study was: Are there genetic alte ...[more]

PMID: 32856014

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Project description:UnlabelledSirtuin 6 (SIRT6) is a member of the sirtuin family of NAD+-dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. The role of SIRT6 in development and progression of hepatocellular carcinoma is currently unknown. We first investigated SIRT6 expression in 153 primary human liver cancers and in normal and cirrhotic livers using microarray analysis. SIRT6 was significantly down-regulated in both cirrhotic livers and cancer. A Sirt6 knockout (KO) gene expression signature was generated from primary hepatoctyes isolated from 3-week-old Sirt6-deficient animals. Sirt6-deficient hepatocytes showed up-regulation of established hepatocellular carcinoma (HCC) biomarkers alpha-fetoprotein (Afp), insulin-like growth factor 2 (Igf2), H19, and glypican-3. Furthermore, decreased SIRT6 expression was observed in hepatoma cell lines that are known to be apoptosis-insensitive. Re-expression of SIRT6 in HepG2 cells increased apoptosis sensitivity to CD95-stimulation or chemotherapy treatment. Loss of Sirt6 was characterized by oncogenic changes, such as global hypomethylation, as well as metabolic changes, such as hypoglycemia and increased fat deposition. The hepatocyte-specific Sirt6-KO signature had a prognostic impact and was enriched in patients with poorly differentiated tumors with high AFP levels as well as recurrent disease. Finally, we demonstrated that the Sirt6-KO signature possessed a predictive value for tumors other than HCC (e.g., breast and lung cancer).ConclusionLoss of SIRT6 induces epigenetic changes that may be relevant to chronic liver disease and HCC development. Down-regulation of SIRT6 and genes dysregulated by loss of SIRT6 possess oncogenic effects in hepatocarcinogenesis. Our data demonstrate that deficiency in one epigenetic regulator predisposes a tumorigenic phenotype that ultimately has relevance for outcome of HCC and other cancer patients.

Dataset Information

Oxytocin receptor genetic alterations in hepatocellular carcinoma.

Publications

Oxytocin receptor genetic alterations in hepatocellular carcinoma.

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