Large-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines.
MicroRNAs (miRNAs) have been found to be involved in cancer initiation, progression and metastasis and, as such, have been suggested as tools for cancer detection and therapy. In this work, a large-scale screening of the complete miRNA mimics library demonstrated that hsa-miR-15a-3p had a pro-apoptotic role in the following human cancer cells: HeLa, AsPc-1, MDA-MB-231, KB3, ME180, HCT-116 and A549. MiR-15a-3p is a novel member of the pro-apoptotic miRNA cluster, miR-15a/16, which was found to activate Caspase-3/7 and to cause viability loss in B/CMBA.Ov cells during preliminary screening. Subsequent microarrays and bioinformatics analyses identified the following four anti-apoptotic genes: bcl2l1, naip5, fgfr2 and mybl2 as possible targets for the mmu-miR-15a-3p in B/CMBA.Ov cells. Follow-up studies confirmed the pro-apoptotic role of hsa-miR-15a-3p in human cells by its ability to activate Caspase-3/7, to reduce cell viability and to inhibit the expression of bcl2l1 (bcl-xL) in HeLa and AsPc-1 cells. MiR-15-3p was also found to reduce viability in HEK293, MDA-MB-231, KB3, ME180, HCT-116 and A549 cell lines and, therefore, may be considered for apoptosis modulating therapies in cancers associated with high Bcl-xL expression (cervical, pancreatic, breast, lung and colorectal carcinomas). The capability of hsa-miR-15a-3p to induce apoptosis in these carcinomas may be dependent on the levels of Bcl-xL expression. The use of endogenous inhibitors of bcl-xL and other anti-apoptotic genes such as hsa-miR-15a-3p may provide improved options for apoptosis-modulating therapies in cancer treatment compared with the use of artificial antisense oligonucleotides.
Biotechnology Core Laboratory, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Aliaksandr
A
Druz
Yu-Chi
YC
Chen
Rajarshi
R
Guha
Michael
M
Betenbaugh
Scott E
SE
Martin
Joseph
J
Shiloach
D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
D020413:3' Untranslated Regions; C494811:BCL2L1 protein, human; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D051020:bcl-X Protein; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7
Apoptosis; BCL-XL; Caspase; cancer cells; microRNA