Research Article: MiR-141 Suppresses the Migration and Invasion of HCC Cells by Targeting Tiam1

Date Published: February 13, 2014

Publisher: Public Library of Science

Author(s): Ying Liu, Yi Ding, Jing Huang, Shuang Wang, Wen Ni, Jian Guan, Qisheng Li, Yuqin Zhang, Yanqing Ding, Bin Chen, Longhua Chen, William B. Coleman.

http://doi.org/10.1371/journal.pone.0088393

Abstract

We have demonstrated that T lymphoma invasion and metastasis 1 (Tiam1) gene is associated with the poor prognosis of patients with hepatocellular carcinoma (HCC), and we used a computational approach to identify miR-141 as a Tiam1-targeting microRNA (miRNA). Here, we explored the function of miR-141 and the relationship between miR-141 and Tiam1 gene in HCC.

The miR-141 expression in HCC tissues and cell lines was detected and its roles in regulation of HCC cell proliferation, migration and invasion and target gene expression was investigated. Tiam1 was identified as a novel target of miR-141. Ethics statement: our study was approved by the Nanfang Hospital Medical Ethics Committee Ethics statement. Written informed consent was obtained before collection.

Based on in situ hybridization (ISH) analysis, miR-141 was down-regulated in the same HCC samples. Kaplan-Meier analysis demonstrated that patients with low miR-141 expression had poorer overall survival rate than that of the patients with high miR-141 expression. Furthermore, multivariate Cox regression analysis indicated that miR-141 could serve as an independent prognostic factor in HCC. MiR-141 significantly inhibited in vitro cell proliferation, migration and invasion as proved by gain- and loss- of function studies, while the mRNA and protein levels of Tiam1 were reduced in cells over-expressing miR-141. Moreover, Tiam1 treatment antagonized this effect, while knockdown of Tiam1 by Tiam1 short hairpin RNA (shTiam1) induced inhibitory effects.

These findings indicated that miR-141 functions as a tumor suppressor and inhibits the migration and invasion of HCC cells by targeting Tiam1, which may provide novel prognostic and treatment strategies for HCC patients.

Partial Text

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third cause of cancer-related death, resulting in approximately 600,000 to 1,000,000 deaths annually in the world [1], [2]. Currently, surgical resection and transplantation are the effective treatment approaches for hepatocellular carcinoma [3]. However, the recurrence rate within 2 years in patients who have undergone of tumor resection remains more than 50% [4], [5]. Uncontrolled tumor metastasis, frequent intrahepatic spread and extrahepatic metastasis are the primary causes for the poor prognosis of HCC [6]. Therefore, improved understanding of the molecular mechanisms of HCC invasion and metastasis is essential for the development of new therapeutic strategies.

Until now, several researches have demonstrated that dozens of miRNAs are involved in HCC development and aberrant expression of some specific miRNAs can be used as a prognostic indicator for HCC patients [26]. MiR-141, which belongs to the miR-200 family, was found to be a useful biomarker for the diagnosis of liver malignancies [27]. However, little is known about the in vivo localization of miR-141 in human HCC tissue samples. In this study, we detected the miR-141 expression in the 212 HCC samples that were used in our previous study and analyzed the possible predictive value of miR-141 in patients with HCC based on ISH analyses. This method has recently demonstrated its reliability in predicting prognosis in colon cancer patients [28]. The Kaplan-Meier survival analysis revealed that low expression of miR-141 significantly correlated with a poor prognosis of HCC patients after surgical resection. Furthermore, multivariate Cox regression analysis demonstrated that low miR-141 expression was an independent prognostic factor for poor survival in HCC. Our previous study has shown that over-expression of Tiam1 was associated with decreased disease-free survival of patients with HCC [20]. Taken together, these findings may imply that miR-141 in combination with Tiam1 could improve the accuracy of predicting which HCC individuals may have a poor prognosis. In addition, our contingency table analysis (χ2 test) showed that miR-141 expression was associated with metastasis, which indicates that miR-141 could serve as a useful tool to identify HCC patients at high risk of metastasis. Although several researches have reported the association of miR-141 expression with different carcinoma, the results lack consistency. MiR-141 was found to be up-regulated in ovarian carcinoma [29], colorectal carcinoma [30], nasopharyngeal carcinoma [31], prostate cancer [32] and down-regulated in renal cell carcinoma [33], gastric cancer [34] and breast cancer [35]. These opposing findings substantiate the hypothesis that miR-141 may play different roles as an oncogene or a tumor suppressor gene in different cancer types. To our best knowledge, however, our observations have not been previously reported. Therefore, our data provided a more comprehensive understanding of the role of miR-141 in HCC.

 

Source:

http://doi.org/10.1371/journal.pone.0088393