Metastasis-associated in colon cancer-1 upregulation predicts a poor prognosis of gastric cancer, and promotes tumor cell proliferation and invasion

Abstract

Metastasis-associated in colon cancer-1 (MACC1) is a newly identified oncogene, and little is known about its role in gastric cancer (GC). Our study was performed to investigate whether MACC1 influences the prognosis of GC patients and to explore the potential mechanisms involved. MACC1 expression was verified to be higher in GC tissues than in adjacent nontumorous tissues by Western blotting. A retrospective analysis of 361 GC patients (Stages I-IV) revealed that higher MACC1 expression was associated with more advanced disease, more frequent postoperative recurrence, more metastases and a higher mortality rate. The disease-free survival of Stage I-III patients and overall survival of Stage-IV patients were significantly worse when their tumors showed high MACC1 expression. To investigate the underlying mechanisms, MACC1 overexpression and downregulation were established in two GC cell lines (BGC-823 and MKN-28 cells). MACC1 overexpression significantly accelerated tumor growth and facilitated metastasis in athymic mice. MACC1 also promoted the proliferation, migration and invasion of both GC cell lines. Moreover, gastric MACC1 mRNA expression levels were significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT) in patients with GC. MACC1 overexpression upregulated mesenchymal-epithelial transition factor and induced changes to markers of EMT, whereas silencing of MACC1 reversed all these changes. These findings provide some novel insights into the role of MACC1, a gene that contributes to a poor prognosis of GC by promoting tumor cell proliferation and invasion as well as the EMT.

Differential role of MACC1 expression and its regulation of the HGF/c-Met pathway between breast and colorectal cancer

“…In the present study, MACC1 expression was associated with prolonged RFS and BCSS in breast cancer patients, which was beyond our expectation and not in agreement with previous studies (8,(10)(11)(12). Additionally, our in vitro studies suggest that MACC1 may not regulate c-Met expression in breast cancer cells, a theory which was also given support by the finding that MACC1 did not bind to the c-Met promoter in MCF7 cells when analyzed by ChIP.…”

“…Consequently MACC1 appears not to contribute to disease progression in breast cancer via HGF/c-Met signaling. MACC1 was first identified as a colon cancer oncogene which promoted metastasis, and to date, a few studies have demonstrated its role in several cancers (8)(9)(10)(11). However, little is known about its role in breast cancer, except for one report by Huang et al (26).…”

“…MACC1 was revealed to be a novel key regulator of tumor growth and metastasis mediated via hepatocyte growth factor (HGF)/c-Met (mesenchymal-epithelial transition factor gene) signaling in colorectal cancers. Increased MACC1 expression has been shown to be correlated with worse survival in several types of cancers, such as colorectal (8,9), hepatocellular (10), gastric (11), and ovarian (12). The HGF/c-Met pathway regulates diverse biological activities, including proliferation, motility, and invasion, many of which are hallmarks of cancer development (13,14).…”

Arsenite promotes intestinal tumor cell proliferation and invasion by stimulating epithelial-to-mesenchymal transition

“…It is now known that metastasis is a multistep process and failure of any step may block the entire metastatic process. 28,29 Although there have been some report suggested that EMT can promote tumor metastasis both in vitro and in vivo, 30,31 little is known what low-dose AS would affect colon cancer cells.…”

MACC1 and HGF are associated with survival in patients with gastric cancer

“…MACC1 is reported to be associated with distant metastasis in gastric cancer (5 by activating the hepatocyte growth factor (HGF)/MET proto-oncogene (c-Met) signaling pathway (6). Overexpression of MACC1 increases invasion in cancer cells by enhancing epithelial-mesenchymal transition (EMT) (7), and is significantly correlated to decreased overall survival (OS) and disease-free survival (DFS) (8). These previous studies, therefore, suggest that MACC1 may have a significant role in promoting tumor metastases.…”