LAPTM4B (lysosomal protein transmembrane 4 beta) is a newly identified cancer-associated gene. Both of its mRNA and the encoded LAPTM4B-35 protein are significantly upregulated with more than 70% frequency in a wide variety of cancers. The LAPTM4B-35 level in cancer is evidenced to be an independent prognostic factor and its upregulation promotes cell proliferation, migration and invasion, as well as tumorigenesis in nude mice. In contrary, knockdown of LAPTM4B-35 expression by RNA interference (RNAi) reverses all of the above malignant phenotypes. We herein reveal a new role of LAPTM4B-35 in promoting multidrug resistance of cancer cells. Upregulation of LAPTM4B-35 motivates multidrug resistance by enhancement of efflux from cancer cells of a variety of chemodrugs with variant structures and properties, including doxorubicin, paclitaxel and cisplatin through colocalization and interaction of LAPTM4B-35 with multidrug resistance (MDR) 1 (P-glycoprotein, P-gp), and also by activation of PI3K/AKT signaling pathway through interaction of PPRP motif contained in the N-terminus of LAPTM4B-35 with the p85a regulatory subunit of PI3K. The specific inhibitors of PI3K and knockdown of LAPTM4B-35 expression by RNAi eliminate the multidrug resistance effect motivated by upregulation of LAPTM4B-35. In conclusion, LAPTM4B-35 motivates multidrug resistance of cancer cells by promoting drug efflux through colocalization and interaction with P-gp, and anti-apoptosis by activating PI3K/AKT signaling. These findings provide a promising novel strategy for sensitizing chemical therapy of cancers and increasing the chemotherapeutic efficacy through knockdown LAPTM4B-35 expression by RNAi.

miRNAs (microRNAs) are frequently and aberrantly expressed in many cancers. MiR-873 has been revealed to be downregulated in colorectal cancer and glioblastoma. However, its function remains unclear. Here we report that miR-873 is downregulated in breast tumor compared with normal tissue. Enforced expression of miR-873 decreases the transcriptional activity of ER (estrogen receptor)-α but not ERβ through the modulation of ERα phosphorylation in ER-positive breast cancer cells. We also found that miR-873 inhibits breast cancer cell proliferation and tumor growth in nude mice. Reporter gene assays revealed cyclin-dependent kinase 3 (CDK3) as a direct target of miR-873. CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3. Interestingly, miR-873 was observed to be downregulated in tamoxifen-resistant MCF-7/TamR cells, while CDK3 is overexpressed in these cells. More importantly, re-expression of miR-873 reversed tamoxifen resistance in MCF-7/TamR cells. Our data demonstrate that miR-873 is a novel tumor suppressor in ER-positive breast cancer and a potential therapeutic approach for treatment of tamoxifen-resistant breast cancer.

No abstract

Antiphospholipid antibodies, including anti-

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...