Novel Epigenetic CREB-miR-630 Signaling Axis Regulates Radiosensitivity in Colorectal Cancer.
BACKGROUND
miR-630 has been reported to be a modulator of several cancers, but the mechanism by which is it influences radioresistance remains unknown. We aimed to identify the molecular function of miR-630 and its regulatory mechanism in colorectal cancer (CRC) cell lines.


METHODS
Overexpression and loss-of-function analyses of miR-630 were performed in CRC cell lines by measuring their levels of growth and apoptosis after ionic radiation (IR). Target genes were detected via a dual-luciferase assay and Western blot. Chromatin immunoprecipitation assay was carried out to identify the transcription factor regulating miR-630, and a demethylation experiment was also conducted.


RESULTS
miR-630 expression was found to be positively correlated with radiosensitivity in CRC cell lines (p<0.05). After IR treatment, miR-630 induced apoptosis in cells; however, the opposite was observed when miR-630 was downregulated (p<0.05). BCL2L2 and TP53RK were identified as the target genes of miR-630, and the function of miR-630 was found to depend on these two genes (p<0.05). In addition, evidence showed that CREB regulates the level of miR-630, and demethylation can elevate miR-630 levels (p<0.05).


CONCLUSIONS
CREB-miR-630-BCL2L2 and TP53RK comprise a novel signaling cascade regulating radiosensitivity in CRC cell lines by inducing cell apoptosis and death.
Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, China.
Yan
Y
Zhang
Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, China.
Jiang
J
Yu
Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, China.
Hao
H
Liu
Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, China.
Wenhui
W
Ma
Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, China.
Li
L
Yan
Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, China.
Jiefu
J
Wang
Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, China.
Guoxin
G
Li
D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D053178:Caspase 6 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000532:radiotherapy; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D035683:MicroRNAs / Q000378:metabolism*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; C548399:MIRN630 microRNA, human; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; C441644:TP53RK protein, human; D053148:Caspase 3; D053178:Caspase 6