Inflection of Akt/mTOR/STAT-3 cascade in TNF-α induced protein 8 mediated human lung carcinogenesis

Lung cancer is the leading cause of cancer-related death across the globe. Despite the marked advances in detection and therapeutic approaches, management of lung cancer patients remains a major challenge to oncologists which can be mainly attributed to late stage diagnosis, tumor recurrence and chemoresistance. Therefore, to overthrow these limitations, there arises a vital need to develop effective biomarkers for the successful management of this aggressive cancer type. Notably, TNF-alpha induced protein 8 (TIPE), a nuclear factor-kappa B (NF-kappa B)-inducible, oncogenic molecule and cytoplasmic protein which is involved in the regulation of T lymphocyte-mediated immunity and different processes in tumor cells such as proliferation, cell death and evasion of growth suppressors, might serve as one such biomarker which would facilitate effective management of lung cancer. Expression studies revealed this protein to be significantly upregulated in different lung cancer types, pathological conditions, stages and grades of lung tumor compared to normal human lung tissues. In addition, knockout of TIPE led to the reduced proliferation, survival, invasion and migration of lung cancer cells. Furthermore, TIPE was found to function through modulation of Akt/mTOR/STAT-3 signaling cascade. This is the first report which shows the involvement of TIPE in tobacco induced lung carcinogenesis. It positively regulated nicotine, NNK, NNN, and BaP induced proliferation, survival and migration of lung cancer cells possibly via Akt/STAT-3 signaling. Thus, this protein possesses important role in the pathogenesis of lung tumor and hence it can be targeted for developing newer therapeutic interventions for the clinico-management of lung cancer.