Telomerase is a ribonucleoprotein that participates in telomere maintenance. Telomerase protein component (hTERT) has been significantly involved in cancer cell survivability and proliferation. c-MET is a heterodimeric receptor protein consisting of extracellular α-subunit along with a β-subunit comprised of the extracellular, transmembrane and intracellular domains. It is activated by its ligand HGF in both paracrine and autocrine manner that triggers downstream signaling pathways; like PI3K, Gab1, STAT, and β-catenin. c-MET is overexpressed in most of cancer cells.
A549, H1299, and HCT116 cancer cells were used for investigation. RNA interference and expression vectors were used in the study. Gene expression was assayed by real-time PCR, western blotting, and immunofluorescence.
hTERT down-regulation by shRNA causes a reduction in c-MET expression while hTERT overexpression increases the c-MET level in the cell. The low luciferase activity of c-MET promoter under hTERT reduced cells reflects the transcriptional regulation of the receptor protein. The c-MET promoter has known p53 binding elements, and hTERT has the negative association with p53 expression in cancer cells. To understand this crosstalk, we overexpressed p53 in A549 and H1299 cells that reflected the decreased expression of c-MET while p53 knockdown caused increased c-MET expression. Further, c-MET and hTERT knockdown have shown slow growth, proliferation and migration potential in both A549 and H1299 cells.
hTERT is differentially overexpressed in 90% of cancer cells. Its negative association with p53 helps in proliferation and survivability. Here, we have for the first time shown that c-MET is positively associated with hTERT expression in cancer cells. This hTERT dependant c-MET expression is mainly controlled by p53 that acts as a repressor in the c-MET promoter. Our findings suggest that the increased expression of hTERT in cancer cells downregulate p53 that triggers the c-MET expression in cells. The increased c-MET expression results in high proliferation, growth, and invasive potential in cancer cells. Although it is a preliminary finding, it suggests its role in cancer aggressiveness which makes this pathway significant in cancer therapeutics.
Clinical trial identification
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Prof. Pramod Kumar Yadava
Department of Science & Technology, Jawaharlal Nehru University, University Grants Commission.
All authors have declared no conflicts of interest.