miRNA‐106a and prostate cancer radioresistance: a novel role for LITAF in ATM regulation

Abstract

Recurrence of high‐grade prostate cancer after radiotherapy is a significant clinical problem, resulting in increased morbidity and reduced patient survival. The molecular mechanisms of radiation resistance are being elucidated through the study of microRNA (miR) that negatively regulate gene expression. We performed bioinformatics analyses of The Cancer Genome Atlas (TCGA) dataset to evaluate the association between miR‐106a and its putative target lipopolysaccharide‐induced TNF‐α factor (LITAF) in prostate cancer. We characterized the function of miR‐106a through in vitro and in vivo experiments and employed transcriptomic analysis, western blotting, and 3′UTR luciferase assays to establish LITAF as a bona fide target of miR‐106a. Using our well‐characterized radiation‐resistant cell lines, we identified that miR‐106a was overexpressed in radiation‐resistant cells compared to parental cells. In the TCGA, miR‐106a was significantly elevated in high‐grade human prostate tumors relative to intermediate‐ and low‐grade specimens. An inverse correlation was seen with its target, LITAF. Furthermore, high miR‐106a and low LITAF expression predict for biochemical recurrence at 5 years after radical prostatectomy. miR‐106a overexpression conferred radioresistance by increasing proliferation and reducing senescence, and this was phenocopied by knockdown of LITAF. For the first time, we describe a role for miRNA in upregulating ATM expression. LITAF, not previously attributed to radiation response, mediates this interaction. This route of cancer radioresistance can be overcome using the specific ATM kinase inhibitor, KU‐55933. Our research provides the first report of miR‐106a and LITAF in prostate cancer radiation resistance and high‐grade disease, and presents a viable therapeutic strategy that may ultimately improve patient outcomes.

<p>Knockdown of lncRNA TUG1 Enhances Radiosensitivity of Prostate Cancer via the TUG1/miR-139-5p/SMC1A Axis</p>

“…Radiation was carried out using a Faxitron 43855F X-ray Irradiator (Faxitron Bioptics LLC, Tucson, AZ, USA) and 2, 4, 6, and 8 Gy radiation were used to treat PCa cells as previously described. 21 Quantitative Real-Time PCR TRIzol reagent kit (Thermo Fisher Scientific, Waltham, MA, USA) was used to extract total RNA from PCa tissues and cells according to the manufacturer's instructions. Allin-One™ miRNA qRT-PCR Detection Kit (GeneCopoeia, FulenGen, China) was used for the synthesis of complementary DNA (cDNA).…”

Regulation of DNA Damage Response and Homologous Recombination Repair by microRNA in Human Cells Exposed to Ionizing Radiation

“…Several miRNAs that sensitize cells to IR by targeting the 3′-UTR of ATM have been identified in cancer cells. Upregulated miRNAs include the following: miR-18a [103], miR-26a [104], miR-27a [105], miR-100 [106], miR-101 [107], miR-106a [108,109], miR-203 [110], miR-223 [111], and miR-421 [112], leading to the suppression of the ATM gene and formation of its protein product at nuclear foci. Furthermore, miR-421 is upregulated by the proto-oncogene protein, N-Myc, transcription factor that establishes some signaling cascades (miR-421/N-Myc/ATM) that causes cell radiosensitivity [112].…”

“…HR repair activation is mediated through the ATM/Chk2/p53 signaling pathway and requires many protein factors (BRCA1, BRCA2, PALB2) and RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) for the proper post-translational modification of RAD51 and accurate repair after irradiation [142,143]. Manipulation of HR mechanism by using miRNAs regulation leads to a clear increase in radiosensitivity or IR-resistance promotion in many cancer cell lines [103,104,108,144,145]. For example, irradiation may promote RAD51 expression by downregulating miR-193b-3p in hepatocytes, whereas than the miRNAs (miR-1255b, miR-148b* and miR-193b*) are inhibited, the increased expression of BRCA1, BRCA2 and RAD51 is detected [123,146].…”

“…MiRNAs induced significant changes in expression profiles. [65,108,109,123] It is important to note that IR induces RAD51 nuclear foci formation, which is cell cycle-dependent [153]. The regulation of HR proteins by specific miRNAs may promote genomic instability after IR exposure.…”

MicroRNA‐488 inhibits proliferation and glycolysis in human prostate cancer cells by regulating PFKFB3

“…In addition, recent studies have demonstrated that miRNAs regulate the functions of various PCa cells during PCa progression [4][5][6][7], and the relationship between PCa and miRNAs has been gradually dissected. However, as miRNAs are widely involved in various cellular functions of PCa, it is necessary to further study miR-NAs and clarify their functions [4,[8][9][10].…”