TIPE2 Induced the Proliferation, Survival, and Migration of Lung Cancer Cells Through Modulation of Akt/mTOR/NF-κB Signaling Cascade.

Devivasha Bordoloi,Ganesan Padmavathi,Choudhary Harsha,Alan Prem Kumar,Hong Wang,Nand Kishor Roy,Rajesh Vikkurthi,Ajaikumar B Kunnumakkara,Javadi Monisha,Kishore Banik,Anuj Kumar Singh

doi:10.3390/biom9120836

Abstract

Lung cancer represents the most common cause of cancer deaths in the world, constituting around 11.6% of all new cancer cases and 18.4% of cancer-related deaths. The propensity for early spread, lack of suitable biomarkers for early diagnosis, as well as prognosis and ineffective existing therapies, contribute to the poor survival rate of lung cancer. Therefore, there is an urgent need to develop novel biomarkers for early diagnosis and prognosis which in turn can facilitate newer therapeutic avenues for the management of this aggressive neoplasm. TIPE2 (tumor necrosis factor-α-induced protein 8-like 2), a recently identified cytoplasmic protein, possesses enormous potential in this regard. Immunohistochemical analysis showed that TIPE2 was significantly upregulated in different stages and grades of lung cancer tissues compared to normal lung tissues, implying its involvement in the positive regulation of lung cancer. Further, knockout of TIPE2 resulted in significantly reduced proliferation, survival, and migration of human lung cancer cells through modulation of the Akt/mTOR/NF-κB signaling axis. In addition, knockout of TIPE2 also caused arrest in the S phase of the cell cycle of lung cancer cells. As tobacco is the most predominant risk factor for lung cancer, we therefore evaluated the effect of TIPE2 in tobacco-mediated lung carcinogenesis as well. Our results showed that TIPE2 was involved in nicotine-, nicotine-derived nitrosamine ketone (NNK)-, N-nitrosonornicotine (NNN)-, and benzo[a]pyrene (BaP)-mediated lung cancer through inhibited proliferation, survival, and migration via modulation of nuclear factor kappa B (NF-κB)- and NF-κB-regulated gene products, which are involved in the regulation of diverse processes in lung cancer cells. Taken together, TIPE2 possesses an important role in the development and progression of lung cancer, particularly in tobacco-promoted lung cancer, and hence, specific targeting of it holds an enormous prospect in newer therapeutic interventions in lung cancer. However, these findings need to be validated in the in vivo and clinical settings to fully establish the diagnostic and prognostic importance of TIPE2 against lung cancer.

Highlights

Lung cancer represents one of the most prevalent cancers in the world, which develops in a multi-stage process via a series of genetic and epigenetic variations in the lung epithelial cells [1,2,3,4,5,6,7].It constitutes approximately 11.6% of all new cancer cases and around 18.4% of total cancer-related deaths across the globe [8]
Our analysis revealed that Tumor Necrosis Factor-α-Induced Protein 8-Like 2 (TIPE2) was significantly upregulated in lung cancer tissues compared to normal lung tissues
Expression analysis of TIPE2 in normal, small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC) tissue samples showed that TIPE2 was upregulated in both SCLC and NSCLC tissues compared to normal tissues, with more pronounced and significant upregulation in the NSCLC type (Figure 1B)

Summary

Introduction

Lung cancer represents one of the most prevalent cancers in the world, which develops in a multi-stage process via a series of genetic and epigenetic variations in the lung epithelial cells [1,2,3,4,5,6,7]. It constitutes approximately 11.6% of all new cancer cases and around 18.4% of total cancer-related deaths across the globe [8]. NSCLC represents the most genomically diverse type, constituting around 80–85% of total lung cancer cases and is associated with challenges in prevention and treatment strategies [1,16,17,18]

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