TCRP1 transcriptionally regulated by c-Myc confers cancer chemoresistance in tongue and lung cancer

Xiaoting Jia,Minying Lu,Zhijie Zhang,Huisi Qiu,Kai Luo,Ying Song,Guopei Zheng,Zhimin He,Hao Liu

doi:10.1038/s41598-017-03763-0

Abstract

Previously, we cloned a new gene termed ‘tongue cancer resistance-associated protein 1’ (TCRP1), which modulates tumorigenesis, enhances cisplatin (cDDP) resistance in cancers, and may be a potential target for reversing drug resistance. However, the mechanisms for regulating TCRP1 expression remain unclear. Herein, we combined bioinformatics analysis with luciferase reporter assay and ChIP assay to determine that c-Myc could directly bind to TCRP1 promoter to upregulate its expression. TCRP1 upregulation in multidrug resistant tongue cancer cells (Tca8113/PYM) and cisplatin-resistant A549 lung cancer cells (A549/DDP) was accompanied by c-Myc upregulation, compared to respective parental cells. In tongue and lung cancer cells, siRNA-mediated knockdown of c-Myc led to decrease TCRP1 expression, whereas overexpression c-Myc did the opposite. Moreover, TCRP1 knockdown attenuated chemoresistance resulting from c-Myc overexpression, but TCRP1 overexpression impaired the effect of c-Myc knockdown on chemosensitivity. Additionally, in both human tongue and lung cancer tissues, c-Myc protein expression positively correlated with TCRP1 protein expression and these protein levels were associated with worse prognosis for patients. Combined, these findings suggest that c-Myc could transcriptionally regulate TCRP1 in cell lines and clinical samples and identified the c-Myc-TCRP1 axis as a negative biomarker of prognosis in tongue and lung cancers.

Highlights

Cancer is becoming a serious public health problem in the world
We demonstrate that c-Myc transcriptionally upregulates tongue cancer resistance-associated protein 1 (TCRP1) in tongue and lung cancer cells through bioinformatics analysis combining with experimental validation
This data demonstrated that TCRP1 was transcriptionally regulated by c-Myc directly binding to its promoter

Summary

Introduction

Cancer is becoming a serious public health problem in the world. In USA, it is evaluated that 1,685,210 cases of new cancer and 595,690 cancer-related deaths would be occurred in 20161. To explore the mechanisms of chemoresistance in cancer treatment, our research group previously established a multi-drug resistant cell line Tca8113/PYM derived from human tongue cancer line Tca8113, by stepwise selection using Pingyangmycin (PYM) as an inducing reagent[6]. We found that TCRP1 mediated PI3K/ Akt pathway activation to drive NIH/3T3 cells malignant transformation[12] These previous studies suggest that targeting TCRP1 may be a potential method to reverse drug resistance. Abnormal gene expression is related with changes in multi-stage regulation, such as the change in DNA or chromosome level, transcription, post-transcription, translation, and protein processing. We demonstrate that c-Myc transcriptionally upregulates TCRP1 in tongue and lung cancer cells through bioinformatics analysis combining with experimental validation. We explored the expression relationships between c-Myc and TCRP1 in tongue and lung cancers, and found that c-Myc positively regulated TCRP1 protein expression, and the c-Myc-TCRP1 axis contributes to chemoresistance in tongue and lung cancers

Methods

Results

Conclusion