miR-221 Promotes Epithelial-Mesenchymal Transition through Targeting PTEN and Forms a Positive Feedback Loop with β-catenin/c-Jun Signaling Pathway in Extra-Hepatic Cholangiocarcinoma

Li, Jianguo; Yao, Lei; Li, Guodong; Ma, Donglai; Sun, Chen; Gao, Shuang; Zhang, Ping; Gao, Feng

doi:10.1371/journal.pone.0141168

Cited by 40 publications

(36 citation statements)

References 28 publications

(39 reference statements)

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“…In human umbilical vein endothelial cells, miR-221 is found to inhibit autophagy by modulating a PTEN/Akt signaling pathway (12). miR-221 targeting PTEN/Akt is also reported in several cancer cells during cancer development (33)(34)(35). Our results implicated a potential role of TP53INP1 on the effect of miR-221 on autophagy of CRC.…”

Section: Discussionsupporting

confidence: 64%

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Liao¹,

Li²,

Ye³

et al. 2017

Exp Ther Med

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Abstract. Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated mortalities worldwide. MicroRNAs (miRNAs/miRs) serve important roles in tumor development, progression and metastasis. miR-221 has been reported to modulate proliferation, apoptosis, cell cycle distribution and cell migration in a variety of cancers. However, the function of miR-221 in the autophagy of cancer is unclear. In the present study, the role of miR-221 in the autophagy of CRC cells was investigated and its associated target was identified. Survival analysis using The Cancer Genome Atlas data suggested that a higher expression of miR-221 was associated with poor survival in patients with CRC. A Cell Counting kit-8 assay revealed that miR-221 promoted CRC cell proliferation. Autophagy flux analyzed by microtubule-associated protein 1 light chain 3 (LC3) turnover indicated that miR-221 reduced autophagy in CRC cells using different protease inhibitors (E64d and pepstatin A; Bafilomycin A1) in nutrient-rich medium or under starvation conditions. Tumor protein 53-induced nuclear protein 1 (TP53INP1) was identified as a potential novel target of miR-221 by bioinformative prediction. The protein expression of TP53INP1 was inversely regulated by miR-221 in CRC cells. Furthermore, luciferase activity assays were performed and indicated that miR-221 may regulate the luciferase activity of wild-type TP53INP1 without interfering with the activity of mutant TP53INP1. These data suggested that miR-221 may promote the cell proliferation of CRC via the inhibition of autophagy and targeted TP53INP1. IntroductionColorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated death worldwide (1). The morbidity rates of CRC are increasing substantially in a number of countries within Eastern Asia and Eastern Europe which were previously at low risk (2). The multifactorial etiology of CRC involves lifestyle and dietary factors, such as smoking, red and processed meat consumption, and excessive alcohol consumption (3). Autophagy is a vital transformational switch among mechanisms that are involved in the pathogenesis of CRC (4). Autophagy may act as a suppressor during early stages and as a promoter during advanced stages of CRC (4,5). It is important to determine the regulative mechanisms of autophagy in CRC.Recent studies suggests that the post-transcription and translation regulation mediated by microRNAs (miRNAs/miRs) contribute significantly to autophagy in cancer (6). It is found that miR-23b-3p inhibits autophagy in gastric cancer cells (7) and miR-26 suppresses autophagy in hepatocellular carcinoma cells (8). Whereas miR-193b is suggested to induce autophagy in oesophageal cancer cells (9). It is interesting that different miRNAs play diverse roles in the regulation of autophagy through various targets.

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Section: Discussionsupporting

confidence: 64%

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Liao¹,

Li²,

Ye³

et al. 2017

Exp Ther Med

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“…Figure 2E) miRs are deeply involved in EMT regulation [14]. So far, 6 miRs including miR-221 [111], mir- …”

Section: Hedgehog Signaling Upon Hedgehog Ligand Binding Gpcr-like mentioning

confidence: 95%

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

124

122

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Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

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“…Specifically, miR-34a 163 , miR-122 164 , miR-140-5p 165 , miR-144 162 , miR-200c 166 , miR-204 167 , miR-212 168 , miR-214 169 , and miR-605 170 negatively regulate CCA cell migration/invasion and consistently, are frequently down-regulated in neoplastic bile ducts. Conversely, miR-21 161,171,172 , miR-181c 173 , and miR-221 174 are up-regulated in CCA, and promote the gain of invasive functions by cancer cells. Of note, the aberrant expression of miRNAs does not necessarily result from cytogenetic abnormalities in miRNA chromosomal sites, but it could also reflect the activation of concomitant pro-oncogenic pathways.…”

Section: Regulation Of Cholangiocarcinoma Invasiveness By Micrornasmentioning

confidence: 99%

“…Of note, the aberrant expression of miRNAs does not necessarily result from cytogenetic abnormalities in miRNA chromosomal sites, but it could also reflect the activation of concomitant pro-oncogenic pathways. For instance, the down-regulation of miR-605 may occur downstream of p53 loss 170 , whereas the up-regulation of miR-221 and miR-181c may be induced by the nuclearization of β-catenin 174 , and by the overproduction of the pro-inflammatory cytokine leukemia inhibitory factor (LIF) 173 , respectively.…”

Section: Regulation Of Cholangiocarcinoma Invasiveness By Micrornasmentioning

confidence: 99%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

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miR-221 Promotes Epithelial-Mesenchymal Transition through Targeting PTEN and Forms a Positive Feedback Loop with β-catenin/c-Jun Signaling Pathway in Extra-Hepatic Cholangiocarcinoma

Cited by 40 publications

References 28 publications

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

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