Abstract
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.
Highlights
Esophageal cancer is the eighth most common cancer worldwide, and accounts for 3.2% of all carcinomas and 4.9% of all carcinoma-related deaths
MiR-193a-5p expression level was inversely correlated with ERBB2, and low miR-193a-5p expression was correlated with poor prognosis in esophageal squamous cell carcinoma (ESCC) patients
To evaluate whether ERBB2 is a good biomarker of prognosis for ESCC patients, immunohistochemistry was used to detect the expression of ERBB2 in 131 ESCC patients
Summary
Esophageal cancer is the eighth most common cancer worldwide, and accounts for 3.2% of all carcinomas and 4.9% of all carcinoma-related deaths. Esophageal cancer patients face two- and fiveyear survival rates of only 50% and 20%, respectively [3]. Because of these high rates of occurrence and mortality, esophageal cancer requires more effective treatment strategies. The National Comprehensive Cancer Network guidelines for esophageal and esophagogastric junction cancers indicate that surgery and concurrent chemoradiation therapy (CCRT) are the primary treatments for cancer of the esophagus. Patients with late stage disease usually cannot undergo surgery due to cancer cell invasion into the aorta, vertebral body, or trachea. Previous studies have demonstrated better survival rates for esophageal cancer patients after receiving CCRT compared with radiation therapy alone [4, 5]. The identification of molecules involved in both tumorigenesis and regulation of the CCRT response may lead to improved therapies for esophageal cancer
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