miR-337-3p and its targets STAT3 and RAP1A modulate taxane sensitivity in non-small cell lung cancers.
NSCLC (non-small cell lung cancer) often exhibits resistance to paclitaxel treatment. Identifying the elements regulating paclitaxel response will advance efforts to overcome such resistance in NSCLC therapy. Using in vitro approaches, we demonstrated that over-expression of the microRNA miR-337-3p sensitizes NCI-H1155 cells to paclitaxel, and that miR-337-3p mimic has a general effect on paclitaxel response in NSCLC cell lines, which may provide a novel adjuvant strategy to paclitaxel in the treatment of lung cancer. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p on paclitaxel sensitivity. Further investigation showed that miR-337-3p mimic also sensitizes cells to docetaxel, another member of the taxane family, and that STAT3 levels are significantly correlated with taxane resistance in lung cancer cell lines, suggesting that endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC.
Greehey Children's Cancer Research Institute, UT Health Science Center at San Antonio, San Antonio, Texas, USA.
Liqin
L
Du
Maria C
MC
Subauste
Christopher
C
DeSevo
Zhenze
Z
Zhao
Michael
M
Baker
Robert
R
Borkowski
Jeoffrey J
JJ
Schageman
Rachel
R
Greer
Chin-Rang
CR
Yang
Milind
M
Suraokar
Ignacio I
II
Wistuba
Adi F
AF
Gazdar
John D
JD
Minna
Alexander
A
Pertsemlidis
D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics*; D043823:Taxoids / Q000494:pharmacology; D020827:rap1 GTP-Binding Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D035683:MicroRNAs; C544075:Mirn337 microRNA, human; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D043823:Taxoids; C080625:taxane; D020827:rap1 GTP-Binding Proteins; D017239:Paclitaxel