MACC1 promotes carcinogenesis of colorectal cancer via β-catenin signaling pathway.

Tiantian Zhen,Anjia Han,Huijuan Shi,Dongjie Yang,Hui Li,Sujuan Dai,Lili Kang,Yulong He,Shirong Cai,Yingjie Liang,Fenfen Zhang,Yang Yang

doi:10.18632/oncotarget.1993

Tiantian Zhen, Anjia Han + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.1993

Copy DOI

Journal: Oncotarget	Publication Date: May 20, 2014
Citations: 55	License type: cc-by

Affiliation: Sun Yat-sen University

Abstract

Here we confirmed that metastasis-associated in colon cancer 1 (MACC1) and β-catenin expression were higher in colorectal cancer (CRC) cells and tissues than those in normal colonic epithelial cell line and adjacent non-tumour colorectal mucosa (ANM) tissues, respectively. MACC1 expression was significantly related to histological differentiation (p<0.001), UICC stage (p=0.029), T classification (p=0.017), and N classification (p=0.023). Cox regression analysis demonstrated that high MACC1/abnormal β-catenin expression was the strongest independent prognostic indicator for reduced overall survival in CRC patients. Significant positive correlation between MACC1 expression and abnormal β-catenin expression was found in CRC tissues. MACC1 knockdown dramatically inhibited cellular proliferation, migration, invasion, colony formation, and tumorigenesis, both in vitro and in vivo, but induced apoptosis in CRC cells. Further MACC1 over-expression increased Met, β-catenin, and its downstream genes including c-Myc, cyclin D1, and MMP9 expression, and its upstream gene phos-GSK3β (Ser9) expression. In addition, MACC1 increased vimentin and suppressed E-cadherin in HCT116 cells. Silencing of MACC1 reversed all these changes. Our results firstly suggest that MACC1 plays an important role in carcinogenesis and progression of CRC through β-catenin signaling pathway and mesenchymal-epithelial transition.

Highlights

Colorectal cancer (CRC) is one of the most common malignancies worldwide
metastasis-associated in colon cancer 1 (MACC1) and β-catenin protein expressions were higher in CRC cell lines including LOVO, SW1116, SW480, HCT116, SW620, and HT29 compared with human colonic epithelial cell line NCM460 by western blot analysis (Figure 1A)
Real-time polymerase chain reaction (PCR) showed that MACC1 and β-catenin mRNA expression were significantly higher in 12 samples of fresh CRC tissues compared to their respective adjacent non-tumour colorectal mucosa (ANM) tissues

Summary

Introduction

Metastasis-associated in colon cancer-1(MACC1), a newly identified key regulator of hepatocyte growth factor (HGF)-MET signaling, predicts colon cancer metastasis [1,2,3]. MACC1 expression has been found in lung cancer [4], hepatocellular carcinoma [5], ovarian carcinoma [6], gastric carcinoma [7], esophageal cancer [8], and nasopharygneal carcinoma [9]. Overexpression of MACC1 associates with the progression of these carcinomas and prognosis of the patients with these carcinomas [4, 7, 8]. The Wnt/β-catenin signaling pathway could be regulated by other signaling molecules or pathways, including a destruction complex consisting of casein kinase Iα (CKIα), glycogen synthase kinase 3β (GSK3β), adenomatous polyposis coli (APC) and Axin. The transcription of many proto-oncogenes, such as cyclin D1, c-Myc, and human telomerase reverse transcriptase is dramatically suppressed [3, 10,11,12,13,14]

Methods

Results

Conclusion