Upregulation of LAPTM4B‐35 Promotes Malignant Transformation and Tumorigenesis in L02 Human Liver Cell Line

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide and is the second leading cause of cancer death in China. We have previously demonstrated that LAPTM4B-35, encoded by lysosomal protein transmembrane 4 beta gene, is overexpressed in over 80% of HCCs and is a novel-independent prognostic factor for metastasis, recurrence, and postoperative survival in HCC. In this study, we investigated the role of LAPTM4B-35 in malignant transformation and tumorigenesis using L02 cells, a cell line originated from human normal liver cells. Our data show that replication-deficient adenovirus vector-mediated upregulation of LAPTM4B-35 promotes anchorage-independent proliferation and resistance to adriamycininduced apoptosis. Study of the underlying mechanisms demonstrated alterations of molecular events involved in these processes, which included the activation of phosphoinositide 3-kinases (PI3K)/serine/threonine protein kinase B (PKB/AKT)/bcl-xL/bcl-2-associated death promoter homolog (Bad) signaling pathway, inhibition of caspase-3 activation, upregulation of Bcl-2, and downregulation of Bax. In addition, upregulation of LAPTM4B-35 in L02 cells resulted in tumorigenesis in 100% (6/6) of inoculated nude mice and accelerated the death of mice with xenografts in vivo. In conclusion, LAPTM4B-35 promotes malignant transformation and tumorigenesis in human liver L02 cell line through promotion of deregulated proliferation and inhibition of apoptosis. These findings suggest that overexpression of LAPTM4B-35 may play a critical role in hepatocarcinogenesis and therefore, may be a therapeutic target for HCC. Anat Rec, 294:1135Rec, 294: -1142Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

A Kinase-Independent Role for EGF Receptor in Autophagy Initiation

“…LAPTM4B was originally identified in hepatocellular carcinoma patients as an abnormally overexpressed protein and was later found to be upregulated in many other human cancers including breast, lung, ovarian, and colon cancers (Kasper et al, 2005). Ectopic expression of LAPTM4B transforms normal cells and promotes proliferation, migration and invasion of cancer cells (Li et al, 2011a; Yang et al, 2010). LAPTM4B is proposed to promote cancer cell proliferation by upregulating PI3K/ATK signaling (Li et al, 2010a).…”

Increased levels of LAPTM4B, VEGF and survivin are correlated with tumor progression and poor prognosis in breast cancer patients

“…Interestingly, a previous study revealed that tissues with elevated expression of LAPTM4B had significantly more new capillary blood vessels than tissues with reduced expression in a mouse xenograft model of liver cancer, indicating that LAPTM4B over-expression might be significantly associated with increased angiogenic activity [16]. Recent studies have also shown that silencing LAPTM4B remarkably reduces the expression of VEGF in HeLa cells [17] and that increased LAPTM4B-35 combined with positive VEGF expression might serve as a new biological marker to predict outcomes in cervical carcinoma [18].…”

“…Recent studies have also shown that silencing LAPTM4B remarkably reduces the expression of VEGF in HeLa cells [17] and that increased LAPTM4B-35 combined with positive VEGF expression might serve as a new biological marker to predict outcomes in cervical carcinoma [18]. In addition, it has been proven that the upregulation of LAPTM4B-35 promotes the activation of AKT and Bad, which would maintain cell survival [16]. …”

LAPTM4B Targeting as Potential Therapy for Hepatocellular Carcinoma

“…In addition, the overexpression of LAPTM4B-35 leads to the accumulation of a number of oncoproteins and downregulation of a number of tumor suppressing proteins. Conversely, knockdown of endogenous LAPTM4B-35 via RNAi results in remarkable inhibition of xenograft growth and metastasis of human HCC in nude mice [5,7]. Meanwhile, the RNAi knockdown of LAPTN4B-35 can reverse the cellular and molecular malignant phenotypes noted above [5].…”

“…Moreover, HCC cells with a high expression of LAPTM4B-35 show a strong tendency to motivate drug resistance [6]. The over-expression of this gene promotes tumorigenesis, faster growth, and metastasis of human HCC xenografts in nude mice [5,7] and leads to antiapoptosis, deregulation of proliferation, enhancement of migration and invasion, and multidrug resistance [5]. In addition, the overexpression of LAPTM4B-35 leads to the accumulation of a number of oncoproteins and downregulation of a number of tumor suppressing proteins.…”