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Let-7c inhibits cholangiocarcinoma growth but promotes tumor cell invasion and growth at extrahepatic sites.

ABSTRACT: Cholangiocarcinoma (CCA) is a cancer type with high postoperative relapse rates and poor long-term survival largely due to tumor invasion, distant metastasis, and multidrug resistance. Deregulated microRNAs (miRNAs) are implicated in several cancer types including CCA. The specific roles of the miRNA let-7c in cholangiocarcinoma are not known and need to be further elucidated. In our translational study we show that microRNA let-7c expression was significantly downregulated in human cholangiocarcinoma tissues when compared to adjacent tissues of the same patient. Let-7c inhibited the tumorigenic properties of cholangiocarcinoma cells including their self-renewal capacity and sphere formation in vitro and subcutaneous cancer cell growth in vivo. Ectopic let-7c overexpression suppressed migration and invasion capacities of cholangiocarcinoma cell lines in vitro, however, promoted distant invasiveness in vivo. Furthermore, we found that let-7c regulated the aforementioned malignant biological properties, at least in part, through regulation of EZH2 protein expression and through the DVL3/?-catenin axis. The miRNA let-7c thus plays an important dual role in regulating tumorigenic and metastatic abilities of human cholangiocarcinoma through mechanisms involving EZH2 protein and the DVL3/?-catenin axis.

SUBMITTER: Xie Y

PROVIDER: S-EPMC5833708 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Let-7c inhibits cholangiocarcinoma growth but promotes tumor cell invasion and growth at extrahepatic sites.

Xie Yu Y Zhang Hang H Guo Xing-Jun XJ Feng Ye-Chen YC He Rui-Zhi RZ Li Xu X Yu Shuo S Zhao Yan Y Shen Ming M Zhu Feng F Wang Xin X Wang Min M Balakrishnan Asha A Ott Michael M Peng Feng F Qin Ren-Yi RY

Cell death & disease 20180214 2

Cholangiocarcinoma (CCA) is a cancer type with high postoperative relapse rates and poor long-term survival largely due to tumor invasion, distant metastasis, and multidrug resistance. Deregulated microRNAs (miRNAs) are implicated in several cancer types including CCA. The specific roles of the miRNA let-7c in cholangiocarcinoma are not known and need to be further elucidated. In our translational study we show that microRNA let-7c expression was significantly downregulated in human cholangiocar ...[more]

PMID: 29445149

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Project description:BackgroundPatients with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) have limited treatment options and poor prognosis. Tumor-associated macrophages (TAMs) are the most abundant infiltrating immune cells in the tumor microenvironment and promote tumor stemness, proliferation, invasion and metastasis. Evidence suggested that transthyretin (TTR) influenced the prolifetation and invasion functions of different tumors and play an essential role in the tumor microenvironment.AimsTo investigate the involvement of TTR in TAMs affecting the invasion of cHCC-CCA.Methods and resultsData sets obtained from the Gene Expression Omnibus database were integrated. Differentially expressed genes (DEGs) were obtained using R software, and modules associated with cHCC-CCA were screened by weighted gene co-expression network analysis (WGCNA). Human THP-1 cells were induced to differentiate into macrophages and then co-cultured with HCCC9810 cells and tumor necrosis factor-α (TNF-α) to simulate the inflammatory microenvironment of cHCC-CAA. In addition, small interfering RNA against TTR was transfected into HCCC9810 cells, and recombinant TTR and ERK and AKT-specific inhibitors were added to HCCC9810 cells, respectively; after that, the levels of NF-κB protein and phosphorylated ERK and AKT were measured. The invasive abilities of HCCC9810 cells were also tested. One hundred forty-five DEGs were associated with cHCC-CCA, of which TTR was up-regulated. Turquoise modules containing TTR in WGCNA were most significantly associated with cHCC-CCA. TTR was highly expressed in HCCC9810 compared to Huh-28. HCCC9810 showed enhanced invasive capacity after co-culture with TNF-α + macrophages (p < .05). After interfering with TTR, the invasive ability of HCCC9810 was diminished, accompanied by decreased expression of NF-κB, p-ERK1/2, and p-AKT (p < .05). After treating HCCC9810 with ERK and AKT-specific inhibitors, the invasive ability of HCCC9810 was diminished, accompanied by decreased expression of NF-κB and TTR (p < .05).ConclusionTTR can promote the invasive ability of cHCC-CCA by regulating AKT/NF-κB and ERK pathways with the assistance of TAMs.

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Let-7c inhibits cholangiocarcinoma growth but promotes tumor cell invasion and growth at extrahepatic sites.

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Let-7c inhibits cholangiocarcinoma growth but promotes tumor cell invasion and growth at extrahepatic sites.

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