MiR-193a-5p/ERBB2 act as concurrent chemoradiation therapy response indicator of esophageal squamous cell carcinoma
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Cheng-Han Lin1,9,*, Chen-Hsun Tsai2,*, Ching-Tung Yeh1, Jui-Lin Liang1,3, Wan-Chun Hung1, Forn-Chia Lin4, Wei-Lun Chang1,5, Hao-Yi Li1, Yun-Chin Yao6, Tai-I Hsu2, Yu-Cheng Lee2, Yi-Ching Wang7, Bor-Shyang Sheu1,5, Wu-Wei Lai8, Marcus J. Calkins1, Michael Hsiao9, Pei-Jung Lu1,2
1Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
2Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
3Department of General Surgery, Chi-Mei Medical Center, Liouying, Tainan 736, Taiwan
4Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan 704, Taiwan
5Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
6Clinical Medicine Research Center, National Cheng Kung University Hospital, Tainan 704, Taiwan
7Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
8Department of Surgery Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
9Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
*These authors contributed equally to this work
Michael Hsiao, email: [email protected]
Pei-Jung Lu, email: [email protected]
Keywords: miR-193a-5p, ERBB2, CCRT, esophageal squamous cell carcinoma, indicator
Received: October 16, 2015 Accepted: March 31, 2016 Published: May 18, 2016
Concurrent chemoradiation therapy (CCRT) is the predominant treatment in esophageal cancer, however resistance to therapy and tumor recurrence are exceedingly common. Elevated ERBB2/Her2 may be at least partially responsible for both the high rates of recurrence and resistance to CCRT. This receptor tyrosine kinase is upregulated in 10–20% of esophageal squamous cell carcinoma (ESCC) tissues, and amplification of ERBB2 has been correlated with poor prognosis in esophageal cancer. Tissues from 131 ESCC patients, along with cell and animal models of the disease were used to probe the underlying mechanisms by which ERBB2 upregulation occurs and causes negative outcomes in ESCC. We found that overexpression of ERBB2 inhibited radiosensitivity in vitro. Furthermore, miR-193a-5p reduced ERBB2 expression by directly targeting the 3’UTR. Increased miR-193a-5p enhanced radiosensitivity and inhibited tumorigenesis in vitro and in vivo. Additionally, low miR-193a-5p expression correlated with poor prognosis in ESCC patients, and ESCC patients with good CCRT response exhibited higher miR-193a-5p expression. Our data suggest that patients with high miR-193a-5p will likely benefit from CCRT treatment alone, however a combination of CCRT with Herceptin may be beneficial for patients with low miR-193a-5p expression.
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