LAPTM4B‐35, a novel tetratransmembrane protein and its PPRP motif play critical roles in proliferation and metastatic potential of hepatocellular carcinoma cells

Abstract

Lysosomal protein transmembrane 4 beta (LAPTM4B) was originally identified as a hepatocellular carcinoma (HCC)-associated gene. This gene and its protein product LAPTM4B-35, are both overexpressed in a variety of human cancers. However, its specific role in cell transformation and malignancy has remained elusive. In the present study we investigated the effects of LAPTM4B-35 overexpression on the malignant phenotypic features in the HLE cell line. Our data show that overexpression of LAPTM4B-35 promotes cell proliferation, exogenous growth-stimulating factorindependent and anchorage-independent growth, and enhances metastatic potential, including promotion of both cell migration and invasion. Study of the underlying mechanisms demonstrated alterations of molecular events involved in these processes, which included upregulation of proliferation-promoting transcription factors such as c-Myc, c-Jun, and c-Fos, and cell cycle-promoting proteins such as cyclin D1 and cyclin E. In addition, mutagenesis study showed that the PPRP motif in the N-terminal region of LAPTM4B-35 plays a critical role in promoting proliferation, migration, and invasion, as well as in the upregulation of the oncoproteins noted above. These data offer insight into the mechanism by which this novel tetratransmembrane protein contributes to the pathogenesis of liver cancer, and suggest that it may be a potential target for cancer therapy. (Cancer Sci 2009; 100: 2335-2340 O ur previous studies reported a novel HCC-associated gene designated as LAPTM4B by HUGO Gene Nomenclature Committee. The full-length cDNA sequence (NCBI NM_018407, Gene ID = 55353) of LAPTM4B contains two translational initiation codons (ATG) with an interval of 273 bp as predicted by bioinformatics and, therefore, encodes two protein isoforms: LAPTM4B-35 and LAPTM4B-24 with apparent molecular weights of 35 and 24 kDa, respectively, which have been confirmed by western blot analysis.(1,2) The LAPTM4B proteins contain four transmembrane domains, two extracellular domains (EC1 and EC2), and two cytoplasmic tails consisting of the N-terminus and C-terminus of the protein, the latter of which contains typical lysosome-targeting motifs.LAPTM4B-24 shows 46% homology to lysosomal protein transmembrane 4 alpha at the amino acid level.(1,3,4) Human LAPTM4B shares high homology (92%) with its murine counterpart. It also has certain homology to fish and other vetebrates, as well as to some invertebrates such as Drosophila. Therefore, LAPTM4B is a conserved protein in evolution.(1) LAPTM4B mRNA is expressed in a wide range of human normal tissues to various extents; it is especially high in the testis, heart, skeletal muscle, and uterus, but very low in the liver and lungs. Notably, the level of LAPTM4B mRNA determined by northern blot analysis is markedly upregulated in 87.3% (48 ⁄ 55) of HCC, and correlates significantly with the pathological grade and differentiation of HCC.(1) LAPTM4B mRNA is also elevated in a variety of other carcinomas including lung cancer (88%, 23 ⁄ 26), colon can...

Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor β1 (TGF-β1) Production in Human Regulatory T Cells

“…In tumors, it appears to play an oncogenic role. High LAPTM4B levels are associated with poor prognosis in many types of cancers (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41), and in vitro and in vivo analyses of cells in which LAPTM4B was overexpressed or silenced indicate that LAPTM4B favors proliferation, migration, invasion, tumorigenesis, and metastasis (42,43). Two mechanisms by which LAPTM4B plays oncogenic roles have recently been identified.…”

LAPTM4B polymorphism is associated with non-small cell lung cancer susceptibility and prognosis

“…Furthermore, extensive studies have been performed to account for such outcomes. Studies have shown that upregulation of LAPTM4B could promote cell proliferation (28), invasion, migration (29) and may inhibit cell apoptosis (30,31) in vitro, while in nude mice the time of tumorigenesis was markedly shortened (29). It was assumed that various signal molecules were associated with cellular malignant transformation after the alteration of LAPTM4B protein expression level.…”

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

“…LAPTM4B (13.058, DON1/5) expression increase could be confirmed in the liver (fc: 11.77, DON5) and the jejunum (fc: 11.31, DON2.5). LAPTM4B is a tetra-transmembrane glycoprotein localised on endosomes and lysosomes (Liu et al, 2009). LAPTM4B was also upregulated in the early phase of liver regeneration in rats (Xu et al, 2005).…”