Abstract
Extrahepatic cholangiocarcinoma (EHCC) is a refractory malignancy with poor prognosis due to its early invasion, metastasis and recurrence after operation. Therefore, understanding the mechanisms of invasion and metastasis is the key to the development of new and effective therapeutic strategies for EHCC. In the present study we demonstrated that miR-221 promoted EHCC invasion and metastasis through targeting PTEN and formed a positive feedback loop with β-catenin/c-Jun signaling pathway. We found miR-221 was upregulated in EHCC specimens and CC cell lines. Moreover, miR-221 was found strongly associated with the metastasis and prognosis of EHCC patients. The expression of PTEN was downregulated in EHCC patients and CC cell lines, and was further demonstrated as one of the downstream targets of miR-221. In addition, our data indicated that β-catenin activated miR-221 through c-jun, while miR-221 enhanced β-catenin signaling induced-epithelial-mesenchymal transition (EMT) by targeting PTEN, hence forming a positive feedback loop in EHCC cell lines. In conclusion, our results suggested that miR-221 promotes EMT through targeting PTEN and forms a positive feedback loop with β-catenin/c-Jun signaling pathway in EHCC.
Highlights
Extrahepatic Cholangiocarcinoma (EHCC) is a malignant epithelial neoplasm with bile duct epithelial differentiation
MiR-221 Forms Positive Feedback Loop with β-catenin/c-Jun Pathway homolog deleted on chromosome 10; NBD, normal bile duct; miRNA, microRNA; UTR, 3’-untranslated region; EMT, epithelial-mesenchymal transition; BIO, 6-bromoindirubin-3`-oxime; DMSO, Dimethy sulphoxide; GSK3, glycogen synthase kinase 3; qRTPCR, quantitative real time Reverse TranscriptionPCR; DMEM, Dulbelcco’s Modified Eagle Media; FBS, fetal bovine serum; UICC, International Union against Cancer; PBS, Phosphate buffer saline; IRB, Institutional Review Board
Concerning the relationship between miR-221 expression and clinicopathological features, in the present study we found that miR-221 expression was significantly increased in human EHCC tissues and CC cell lines, and miR-221 expression level was associated with risk of relapse and metastasis
Summary
Extrahepatic Cholangiocarcinoma (EHCC) is a malignant epithelial neoplasm with bile duct epithelial differentiation. The intraductal and extraductal invasion, metastasis to regional lymph nodes and liver sites are the PLOS ONE | DOI:10.1371/journal.pone.0141168. MiR-221 Forms Positive Feedback Loop with β-catenin/c-Jun Pathway homolog deleted on chromosome 10; NBD, normal bile duct; miRNA, microRNA; UTR, 3’-untranslated region; EMT, epithelial-mesenchymal transition; BIO, 6-bromoindirubin-3`-oxime; DMSO, Dimethy sulphoxide; GSK3, glycogen synthase kinase 3; qRTPCR, quantitative real time Reverse TranscriptionPCR; DMEM, Dulbelcco’s Modified Eagle Media; FBS, fetal bovine serum; UICC, International Union against Cancer; PBS, Phosphate buffer saline; IRB, Institutional Review Board. Main prognostic factors in EHCC patients [1]. Local and distant recurrences occur in many EHCC patients after resection [2]. It is necessary to elucidate the mechanisms of the invasion and metastasis of EHCC
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