A genetic variation in microRNA target site of ETS2 is associated with clinical outcomes of paclitaxel-cisplatin chemotherapy in non-small cell lung cancer
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Mi Jeong Hong1,2,*, Shin Yup Lee3,4, Jin Eun Choi1,2, Cheng Cheng Jin1, Hyo Jung Kang1, Sun Ah Baek1, So Yeon Lee4, Kyung Min Shin5, Ji Yun Jeong6, Won Kee Lee7, Seung Soo Yoo3,4, Jaehee Lee3, Seung Ick Cha3, Chang Ho Kim3, Ji Woong Son8, Jae Yong Park1,2,3,4,*
1Departments of Biochemistry and Cell Biology, Kyungpook National University Medical Center, Daegu, Republic of Korea
2Cell and Matrix Research Institute, Kyungpook National University Medical Center, Daegu, Republic of Korea
3Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
4Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea
5Department of Radiology, Kyungpook National University Medical Center, Daegu, Republic of Korea
6Department of Pathology, Kyungpook National University Medical Center, Daegu, Republic of Korea
7Biostatistics Center, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
8Department of Internal Medicine, Konyang University Hospital, Daejeon, Republic of Korea
*These authors have contributed equally to this work
Shin Yup Lee, e-mail: firstname.lastname@example.org
Keywords: non-small cell lung cancer, miRNA target sites, polymorphisms, chemotherapy, response
Received: October 02, 2015 Accepted: February 06, 2016 Published: February 17, 2016
The present study was performed to investigate the association of single nucleotide polymorphisms (SNPs) located in the miRNA target sites with the clinical outcomes of first line paclitaxel-cisplatin chemotherapy in advanced NSCLC. Eighty SNPs in miRNA binding sites of cancer related genes selected from 18,500 miRNA:target bindings in crosslinking, ligation, and sequencing of hybrids (CLASH) data were investigated in 379 advanced NSCLC patients using a sequenom mass spectrometry-based genotype assay. qRT-PCR and luciferase assay were conducted to examine functional relevance of potentially functional SNPs in miRNA binding sites. Of the 80 SNPs analyzed, 16 SNPs were significantly associated with the clinical outcomes after chemotherapy. Among these, ANAPC1 rs3814026C>T, ETS2 rs461155A>G, SORBS1 rs7081076C>A and POLR2A rs2071504C>T could predict both chemotherapy response and survival. Notably, ETS2 rs461155A>G was significantly associated with decreased ETS2 mRNA expression in both tumor and paired normal lung tissues (Ptrend = 4 × 10−7, and 3 × 10−4, respectively). Consistently, a decreased expression of the reporter gene for the G allele of rs461155 compared with the A allele was observed by luciferase assay. These findings suggest that the four SNPs, especially ETS2 rs461155A>G, could be used as biomarkers predicting the clinical outcomes of NSCLC patients treated with first-line paclitaxel-cisplatin chemotherapy.
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