TdIF1: a putative oncogene in NSCLC tumor progression

Yujuan Zhang,James Koropatnick,Derong Xu,Keng Yuan,Zhigang Wang,Qi Liu,Yanling Liu,Yifan Wang,Nanjin Zhou,Juan Xiong,Weiping Min,Fan Cao,Rakesh Joshi,Yanqing Huang,Muying Ying,Meng Zhang

doi:10.1038/s41392-018-0030-9

Yujuan Zhang, James Koropatnick + Show 14 more

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https://doi.org/10.1038/s41392-018-0030-9

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TdT-interacting factor 1 (TdIF1) is a ubiquitously expressed DNA- and protein-binding protein that directly binds to terminal deoxynucleotidyl transferase (TdT) polymerase. Little is known about the functional role of TdIF1 in cancer cellular signaling, nor has it previously been identified as aberrant in any type of cancer. We report here for the first time that TdIF1 is abundantly expressed in clinical lung cancer patients and that high expression of TdIF1 is associated with poor patient prognosis. We further established that TdIF1 is highly expressed in human non-small cell lung cancer (NSCLC) cell lines compared to a normal lung cell line. shRNA-mediated gene silencing of TdIF1 resulted in the suppression of proliferation and anchorage-independent colony formation of the A549 adenocarcinoma cell line. Moreover, when these TdIF1-silenced cells were used to establish a mouse xenograft model of human NSCLC, tumor size was greatly reduced. These data suggest that TdIF1 is a potent regulator of lung tumor development. Several cell cycle-related and tumor growth signaling pathways, including the p53 and HDAC1/2 pathways, were identified as participating in the TdIF1 signaling network by in silico analysis. Microarray, transcriptome and protein-level analyses validated p53 and HDAC1/2 modulation upon TdIF1 downregulation in an NSCLC cellular model. Moreover, several other cell cycle regulators were affected at the transcript level by TdIF1 silencing, including an increase in CDKN1A/p21 transcripts. Taken together, these results indicate that TdIF1 is a bona fide tumor-promoting factor in NSCLC and a potential target for therapy.

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Lung cancer is the most common cancer globally, after basal skin cancer, and the deadliest of human cancers
terminal deoxynucleotidyl transferase (TdT)-interacting factor 1 (TdIF1) is upregulated in lung cancer We first performed representational difference analysis with RNASeq information of 57 paired tissues from The Cancer Genome Atlas (TCGA)
We examined the expression of TdIF1 in tumor tissues in non-small cell lung cancer (NSCLC) patients

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INTRODUCTION

Lung cancer is the most common cancer globally, after basal skin cancer, and the deadliest of human cancers. The lack of targetable mutations in 50% of NSCLC underscores the importance of the identification and validation of drugable targets.[4] The identification of novel regulatory molecules in lung cancer progression (biomarkers and/or therapeutic targets) is clinically relevant, allowing for novel diagnostics to be developed for early detection and for effective individual or combined targeted therapies. This strategy forms the foundation of personalized medicine, especially in the therapy of resistant subtypes of cancer.[5,6] A first step is to identify and validate novel molecules, or putative oncogenes, to investigate translational and clinical methodologies.[7]. Celigo image cytometry A549 cells (3 × 105 cells/well) were seeded in 96-well microplates

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