Abstract:
I delineated the functions of Signal Transducer and Activator of Transcription (STAT)- 5A and STAT5B in human mammary carcinoma cells. Overexpression of a constitutively active (CA) variant of STAT5A (CA STAT5A) enhanced survival and anchorageindependent growth of human mammary carcinoma cells but concordantly suppressed cell motility as revealed in colony scattering, cell migration, and invasion assays. Overexpression of CA STAT5B exhibited lower potency than CA STAT5A in enhancing survival and anchorage-independent growth of mammary carcinoma cells but exerted no effects on cell motility. Differential expression of genes that regulate cellular survival and motility was concomitantly observed on overexpression of CA STAT5A or CA STAT5B. Small interfering RNA (siRNA)-mediated depletion of either STAT5A or STAT5B and xenograft analyses provided confirmatory results. Therefore, STAT5A and STAT5B differentially regulate behaviour of human mammary carcinoma cells. I also demonstrated that Artemin (ARTN), one of the glial-cell-line-derived neurotrophic factor (GDNF) family of ligands, promotes progression of human non-small cell lung carcinoma (NSCLC). Information retrieved from Oncomine database indicates that expression of components of ARTN signalling pathway are increased in neoplastic compared to normal lung tissues; increased expression of ARTN also predicted metastasis to lymph nodes and a higher grade in certain NSCLC subtypes. Overexpression of ARTN stimulated survival, anchorage-independent, Matrigel and xenograft growth of NSCLC cell lines. ARTN increased BCL2 expression by transcriptional upregulation and inhibition of BCL2 abrogated the oncogenic properties of ARTN in NSCLC cells. Forced expression of ARTN also enhanced migration and invasion of NSCLC cells. Concordantly, either siRNA-mediated depletion or functional inhibition of endogenous ARTN with antibodies reduced oncogenicity and invasiveness of NSCLC cells. ARTN, therefore, mediates progression of NSCLC and may be a potential therapeutic target for NSCLC. I additionally demonstrated an oncogenic role of STAT3a (the full-length STAT3 isoform), which also mediates the human growth hormone (hGH)-stimulated oncogenicity, in human endometrial carcinoma (EC) cells. Autocrine hGH stimulated Y705 phosphorylation of STAT3 and STAT3-mediated transcriptional activity in a SRC and JAK2 dependent manner. Over expression of a constitutively active variant of STAT3a increased proliferation, anchorage-independent, Matrigel and xenograft growth of EC cells; and promoted epithelial-mesenchymal transition, migration and invasion of these cells. Conversely, JSI-124, a specific inhibitor of STAT3, abrogated the oncogenic capacities of EC cells and the enhancement in the oncogenicities stimulated by hGH. STAT3a may therefore be a common mediator of oncogenic signalling pathways stimulating progression of EC.