Abstract
Mitochondrial transcription factor A (TFAM) is essential for the replication, transcription and maintenance of mitochondrial DNA (mtDNA). The role of TFAM in non-small cell lung cancer (NSCLC) remains largely unknown. Herein, we report that downregulation of TFAM in NSCLC cells resulted in cell cycle arrest at G1 phase and significantly blocked NSCLC cell growth and migration through the activation of reactive oxygen species (ROS)-induced c-Jun amino-terminal kinase(JNK)/p38 MAPK signaling and decreased cellular bioenergetics. We further found that TFAM downregulation in NSCLC cells led to increased apoptotic cell death and enhanced the sensitivity of NSCLC cells to cisplatin. Tissue microarray (TMA) data showed that elevated expression of TFAM was related to the histological grade and TNM stage of NSCLC patients. We also demonstrated that TFAM is an independent prognostic factor for overall survival of NSCLC patients. Taken together, our findings suggest that TFAM could serve as a potential diagnostic biomarker and molecular target for the treatment of NSCLC, as well as for prediction of the effectiveness of chemotherapy.
Highlights
Lung cancer is still the leading cause of cancer-related deaths worldwide, accounting for over 1.37 million deaths annually
TFAM is a member of the high-mobility group (HMG) protein family that is encoded by the nuclear genome and transported into the mitochondrial matrix after translation in the cytoplasm; TFAM is essential for the replication, transcription and maintenance of mitochondrial DNA (mtDNA) [7,8,9,10,11]
Downregulation of TFAM protein and mRNA levels was confirmed by immunoblotting and quantitative real-time PCR, respectively (Figure 1A). mtDNA copy numbers were reduced in TFAM knockdown non-small cell lung cancer (NSCLC) cells, as determined by qRT-PCR (Figure S1A)
Summary
Lung cancer is still the leading cause of cancer-related deaths worldwide, accounting for over 1.37 million deaths annually. There are two main types of lung cancer grouped according to cell morphology, namely small cell lung cancer (SCLC) that is the most aggressive type and accounts for about 15% of all cases and non-small cell lung cancer (NSCLC) that accounts for more than 85% of all cases [1,2,3]. Despite recent improvements in early diagnosis/screening and development of novel therapeutic strategies, the prognosis for all stages of NSCLC is poor: the 5-year survival for all combined stages remains less than 15% due to cancer metastasis at the time of diagnosis and relapse [1, 4,5,6]. TFAM is a member of the high-mobility group (HMG) protein family that is encoded by the nuclear genome and transported into the mitochondrial matrix after translation in the cytoplasm; TFAM is essential for the replication, transcription and maintenance of mtDNA [7,8,9,10,11]
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