MicroRNA-499 serves as a sensitizer for lung cancer cells to radiotherapy by inhibition of CK2α-mediated phosphorylation of p65

Yu-Shui Ma,Bo-Wen Shi,Hai-Min Lu,Peng-Fei Xie,Rui Xin,Zhi-Jun Wu,Yi Shi,Yu-Zhen Yin,Li-Kun Hou,Cheng-You Jia,Wei Wu,Zhong-Wei Lv,Fei Yu,Gao-Ren Wang,Ji-Bin Liu,Geng-Xi Jiang,Da Fu

doi:10.1016/j.omto.2021.03.016

Abstract

The present study aimed to define the tumor-suppressive role of microRNA-499 (miR-499) in lung cancer cells and its underlying mechanism. First, qRT-PCR analysis revealed poor expression of miR-499 in clinical samples and cell lines of lung cancer. Next, we performed loss- and gain-of-function experiments for the expression of miR-499 in lung cancer cells exposed to irradiation (IR) to determine the effect of miR-499 expression on cell viability and apoptosis as well as tumor growth. Results showed that overexpression of miR-499 inhibited cell viability, enhanced the radiosensitivity of lung cancer cells, and promoted cell apoptosis under IR. Furthermore, CK2α was verified to be a target of miR-499, and miR-499 was identified to repress p65 phosphorylation by downregulating CK2α expression, which ultimately diminished the survival rate of lung cancer cells under IR. Collectively, the key findings of the study illustrate the tumor-inhibiting function of miR-499 and confirmed that miR-499-mediated CK2α inhibition and altered p65 phosphorylation enhances the sensitivity of lung cancer cells to IR.

Highlights

Lung cancer remains one of the most frequently diagnosed cancers and ranks first for cancer-related mortality, accounting for nearly 2 million deaths worldwide on an annual basis.[1,2] approximately 20% to 25% of all lung cancer patients are diagnosed at an early disease stage, which is amenable to curative surgery.[3]
It has been reported that miR-499-5p overexpression can inhibit the proliferation and metastasis of non-small cell lung cancer (NSCLC) by targeting VAV3,18 and that miR-499 overexpression can impart poor prognosis by regulating tumor-related gene expression, enhancing tumorigenesis and chemoresistance
In order to verify the correlation between miR-499 expression in lung cancer cells and to clarify its relationship with poor prognoses, we analyzed the expression of miR-499 in lung cancer tissues and adjacent normal tissues by quantitative reverse-transcriptase polymerase chain reaction

Summary

Introduction

Lung cancer remains one of the most frequently diagnosed cancers and ranks first for cancer-related mortality, accounting for nearly 2 million deaths worldwide on an annual basis.[1,2] approximately 20% to 25% of all lung cancer patients are diagnosed at an early disease stage (stage IA–IIIA), which is amenable to curative surgery.[3]. MiRNAs reportedly play a crucial role in the development of lung cancer by regulating various target genes associated with this malignancy.[9] A previous study suggested that the sequence variation of mature miR-499 conferred an adverse prognosis on lung cancer patients.[10] In addition, serum miR-499 has been suggested to be a promising biomarker for early exploration and prognostic prediction of non-small cell lung cancer (NSCLC).[11] In this regard, we speculated that miR-499 might target CK2a and regulate the development of lung cancer. Transcription factors and miRNAs have been reported to have synergistic effects, characterized by unique molecular mechanisms and evolutionary background, which correspond to the two main levels of gene regulatory networks.[12]

Methods

Results

Conclusion