Novel roles of Vmp1: Inhibition metastasis and proliferation of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most deadly human cancers because of its high incidence of metastasis. Despite extensive efforts, therapies against metastasis of HCC remain underdeveloped. Vacuole membrane protein 1 (Vmp1) was recently identified to be involved in cancer-relevant processes; however, its expression, clinical significance and biological function in HCC progression are still unknown. Therefore, we evaluated the expression of Vmp1 in human HCC specimens. To functionally characterize Vmp1 in HCC, we upregulated its expression in HCCLM3 cells using a plasmid transfection approach, following which both in vitro and in vivo models were used to elucidate its role. A significant downregulation of Vmp1 was found in human HCC tissues and closely correlated with multiple tumor nodes, absence of capsular formation, vein invasion and poor prognosis of HCC. Such expression was verified with HCC cell lines including HepG2, MHCC97-L and HCCLM3, and the Vmp1 expression levels negatively correlated with metastatic potential. Interestingly, upregulation of Vmp1 significantly affects proliferation, migration, invasion and adhesion of HCCLM3 cells. Using a mouse model, we demonstrated that upregulation of Vmp1 was associated with suppression of growth and pulmonary metastases of HCC. Therefore, our data suggest Vmp1 is a novel prognostic marker and potential therapeutic target for metastasis of HCC. (Cancer Sci 2012; 103: 2110-2119 H epatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of death from cancer, resulting in more than 600 000 deaths per year.(1,2) During the past decade, the long-term survival rate remains unsatisfactory because of a high incidence of recurrence and metastasis after hepatic resection, with a 5-year actuarial recurrence rate of 75-100% reported in the literature.(3) To predict recurrence, metastasis and prognosis in patients with HCC after hepatic resection is a clinical issue of great significance. Various prognostic markers of HCC have been identified, such as vascular endothelial growth factor (VEGF), osteopontin (OPN) and transforming growth factor-b (TGF-b). Based on a genomic analysis, we previously reported ras homologous gene C (RhoC), high mobility group A1 (HGMA1) and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 (WAVE2) as potential markers for metastasis of HCC.(4-7) All these findings represent significant progress in this field. However, the mechanisms underlying HCC metastasis are still not fully understood, supporting a need for further studies. Thus, exploring new prognostic markers and further inhibition of invasion and metastasis is of great importance in HCC therapies. (8) It is well known that reduced levels of cell-cell adhesion proteins often correlate with tumor invasion and metastasis. (9)

Downregulation of VMP1 confers aggressive properties to colorectal cancer

“…Patients with low VMP1 expression had lower overall survival and disease-free survival than those with high expression of VMP1. Upregulation of VMP1 not only inhibited the proliferation of cancer cells, but also inhibited liver cancer cell metastasis in nude mice (11). The results of the present study and the results in breast and liver cancer are in accordance.…”

“…It is well known that reduced levels of cell-cell adhesion proteins often correlate with tumor invasion and metastasis (22). Guo et al and other studies have shown that upregulation of VMP1 inhibits metastasis of tumor cells (11). However, to date, no studies have shown the impact of VMP1 in colorectal metastases.…”

“…It was first observed in pancreatitis, participating in the process of autophagy (10). Subsequent study of tumor cells demonstrated that it also plays a key role in the development of tumors in processes such as proliferation (11), autophagy (12), metastasis (11) and drug sensitivity (13). A recent study on VMP1 showed that colorectal cancer cells initiated the process of autophagy under the stimulation of rapamycin or lack of nutrients with an increased expression of VMP1 (14).…”

Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV‐related cervical carcinogenesis

“…It has been reported to act as a tumor suppressor in a variety of tumors, including breast, 22 pancreas cancer, 23 as well as in hepatocellular cancer. 24 Because all five integration events categorized in this cohort were located in the intragenic region of TMEM49, it will be interesting to detect in the future whether this gene were commonly mutant in cervical cancers.…”

Association between genetic variants in p53 binding sites and risks of osteosarcoma in a Chinese population: a two-stage case-control study

“…10,11 Normal VMP1 protein expression is necessary to maintain normal tissue homeostasis and integ-rity. 12 At present, a large number of studies have shown that VMP1 involves the development of many tumors, including hepatocellular carcinoma, 13,14 pancreatic cancer, [15][16][17] colorectal cancer, [18][19][20] ovarian cancer, 21 and breast cancer. 22 SNP rs1295925 was located in the p53 transcriptional binding region and its mutation might affect the binding of p53 and eventually lead to different tumor susceptibility.…”