Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52

Abstract

Expression studies have consistently identified tumor protein D52 (TPD52) overexpression in tumor cells. Murine TPD52 (mD52) shares 86% identity with the human orthologue. To study a possible role for TPD52 in transformation, 3T3 fibroblasts were transfected with the full-length cDNA for mD52. Expression of mD52 was confirmed by reverse transcription-PCR (RT-PCR), real-time PCR, and Western blot analysis compared with 3T3 and vector-transfected 3T3 (3T3.V), and the resultant cell line was designated 3T3.mD52. At 4 weeks, 3T3.mD52 gained a 2-fold increase in growth rate, lost contact inhibition, and exhibited a marked phenotype change. Further characterization revealed an acquired ability for anchorage-independent cell growth. To determine whether 3T3.mD52 had become tumorigenic, naïve, healthy, immunocompetent syngeneic mice were inoculated subcutaneously with varying cell doses. Tumors measuring >1 cm 2 were detected 60 days postinoculation with 3T3.mD52, and a 50% subcutaneous tumor incidence was obtained with as few as 5 Â 10 5 3T3.mD52 cells. Remarkably, when lungs from 3T3.mD52 tumor-bearing mice were analyzed, numerous tumor nodules were observed, ranging from nodules less than 10 to nodules too numerous to count (inoculation with 1 Â 10 5 and 5 Â 10 6 cells, respectively). Further support for the metastatic capacity of 3T3.mD52 was the demonstration that transforming growth factor (TGF)-BR1 (receptor) expression decreased and TGF-B1 secretion increased in 3T3.mD52 compared with 3T3 controls. cDNA microarray analysis showed a gene expression pattern that further supported mD52-induced transformation and metastasis. Together, these data suggest that mD52 expression in 3T3 cells initiated cellular transformation, tumorigenesis, and progression to metastasis. (Mol Cancer Res 2007;5(2):133 -44)

Overexpressed oncogenic tumor-self antigens

“…95 Reduction of hD52 expression via RNAi resulted in increased apoptosis in human breast cancer cells, and hD52 overexpression was associated with decreased overall survival in human breast cancer patients. 96 These studies demonstrate that TPD52 overexpression is important for initiating and maintaining an oncogenic and metastatic phenotype and may be important for tumor cell survival.…”

Tumor protein D52 represents a negative regulator of ATM protein levels

“…19 TPD52 promotes proliferation, migration/invasion, and metastasis in different cell models, 17,20,21 whereas knockdown of TPD52 induced apoptosis in breast and prostate cancer cell lines. 17,22 The underlying mechanisms are not yet fully understood, apart from the regulation of Akt/protein kinase B and Stat3/Bcl-2 signaling pathways shown in prostate cancer cell lines.…”

TPD52 expression increases neutral lipid storage within cultured cells

“…At the molecular level, TPD52-like proteins exhibit functional redundancy, in that heterologous partners identified through yeast two-hybrid screens using a single TPD52-like bait also interact with related TPD52-like proteins (Wilson et al, 2001;Proux-Gillardeaux et al, 2003;Shahheydari et al, 2014). However, stable expression of TPD52 or its paralogue TPD52L1 in BALB/c 3T3 cells produced shared but also isoformspecific cellular effects (Lewis et al, 2007;Shehata et al, 2008a). Exogenous TPD52 but not TPD52L1 expression increase the proliferation and anchorage-independent growth of 3T3 cells, whereas both proteins produce similar morphological changes (Shehata et al, 2008a).…”