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Enrichment of cancer stem cells via ?-catenin contributing to the tumorigenesis of hepatocellular carcinoma.

ABSTRACT: BACKGROUND:Hepatocellular carcinoma (HCC) is among the deadliest cancers due to its heterogeneity, contributing to chemoresistance and recurrence. Cancer stem-like cells (CSCs) are suggested to play an important role in HCC tumorigenesis. This study investigates the role of Wnt/?-catenin pathway in CSC enrichment and the capabilities of these CSCs in tumor initiation in orthotopic immunocompetent mouse model. METHODS:HCC-CSCs were enriched using established serum-free culture method. Wnt/?-catenin pathway activation and its components were analyzed by western blot and qRT-PCR. The role of ?-catenin in enrichment of CSC spheroids was confirmed using siRNA interference. Tumorigenic capabilities were confirmed using orthotopic immunocompetent mouse model by injecting 2?×?106 Hepa1-6 CSC spheroids or control cells in upper left liver lobe. RESULTS:The serum-free cultured Hepa1-6 cells demonstrated self-renewal, spheroid formation, higher EpCAM expression, increased Hoechst-33342 efflux, and upregulated Wnt/?-catenin signaling. Wnt/?-catenin pathway upregulation was implicated with the downstream targets, i.e., c-MYC, Cyclin-D1, and LEF1. Also, we found that GSK-3? serine-9 phosphorylation increased in Hepa1-6 spheroids. Silencing ?-catenin by siRNA reversed spheroid formation phenotype. Mice injected with Hepa1-6 CSC spheroids showed aggressive tumor initiation and growth compared with mice injected with control cells. CONCLUSIONS:Successfully induced Hepa1-6 spheroids were identified with CSC-like properties. Aberrant ?-catenin upregulation mediated by GSK-3? was observed in the Hepa1-6 spheroids. The ?-catenin mediated CSC enrichment in the induced spheroids possesses the capability of tumor initiation in immunocompetent mice. Our study suggests plausible cell dedifferentiation mediated by ?-catenin contributes to CSC-initiated HCC tumor growth in vivo.

SUBMITTER: Pandit H

PROVIDER: S-EPMC6091111 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Enrichment of cancer stem cells via β-catenin contributing to the tumorigenesis of hepatocellular carcinoma.

Pandit Harshul H Li Yan Y Li Xuanyi X Zhang Weizhong W Li Suping S Martin Robert C G RCG

BMC cancer 20180803 1

<h4>Background</h4>Hepatocellular carcinoma (HCC) is among the deadliest cancers due to its heterogeneity, contributing to chemoresistance and recurrence. Cancer stem-like cells (CSCs) are suggested to play an important role in HCC tumorigenesis. This study investigates the role of Wnt/β-catenin pathway in CSC enrichment and the capabilities of these CSCs in tumor initiation in orthotopic immunocompetent mouse model.<h4>Methods</h4>HCC-CSCs were enriched using established serum-free culture meth ...[more]

PMID: 30075764

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Project description:BackgroundmiR-500a-3p has been demonstrated to be involved in the development, progression and metastasis in several human cancers. Constitutive activation of JAK/STAT3 signaling pathway has been reported to play an important role in the development and progression of hepatocellular carcinoma (HCC).The purpose of this study was to determine the biological roles and clinical significance of miR-500a-3p in HCC and to identify whether miR-500a-3p has an effect on the activity of JAK/STAT3 signaling in HCC.MethodsmiR-500a-3p expression was examined by real-time PCR in 8 paired HCC tissues and individual 120 HCC tissues respectively. Statistical analysis was performed to explore the clinical correlation between miR-500a-3p expression and clinicopathological features and overall and relapse-free survival in HCC patients. In vitro and in vivo assays were performed to investigate the biological roles of miR-500a-3p in HCC. The bioinformatics analysis, real-time PCR, western blot and luciferase reporter assay were performed to discern and examine the relationship between miR-500a-3p and its potential targets. Clinical correlation of miR-500a-3p with its targets was examined in HCC tissues.ResultsmiR-500a-3p is dramatically elevated in HCC tissues and cells and high expression of miR-500a-3p correlates with poor overall and relapse-free survival in HCC patients. Upregulating miR-500a-3p enhances, while silencing miR-500a-3p suppresses, the spheroid formation ability, fraction of side population and expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further reveal miR-500a-3p promotes the cancer stem cell characteristics via targeting multiple negative regulators of JAK/STAT3 signaling pathway, including SOCS2, SOCS4 and PTPN11, leading to constitutive activation of STAT3 signaling. Moreover, the inhibitory effects of anti-miR-500a-3p on cancer stem cell phenotypes and activity of STAT3 signaling were reversed by silencing SOCS2, SOCS4 and PTPN11 in miR-500a-3p-downexpressing cells, respectively. Clinical correlation of miR-500a-3p with the targets was examined in human HCC tissues.Conclusionour results uncover a novel mechanism by which miR-500a-3p promotes the stemness maintenance of cancer stem cell in HCC, suggesting that silencing miR-500a-3p may serve as a new therapeutic strategy in the treatment of hepatocellular carcinoma.

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Enrichment of cancer stem cells via ?-catenin contributing to the tumorigenesis of hepatocellular carcinoma.

Publications

Enrichment of cancer stem cells via β-catenin contributing to the tumorigenesis of hepatocellular carcinoma.

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