Radioresistance Of Esophageal Carcinoma Research Articles

Promotion of microRNA-146a by histone deacetylase 4 silencing contributes to radiosensitization of esophageal carcinoma

BackgroundHistone deacetylases (HDACs) have been identified to be implicated in the carcinogenesis and cancer progression. The present study was performed to probe into the effect of HDAC4 on radioresistance of esophageal carcinoma (EC).MethodsThe expression of HDAC4 in responders and non-responders to radiotherapy was characterized by RT-qPCR, immunohistochemistry, and Western blot analysis. EC cells were exposed to continuous fractionated X-ray irradiation, and their proliferation and apoptosis were evaluated by means of colony formation assay and flow cytometry based Annexin V-FITC/PI apoptosis assay in response to HDAC4 overexpression or silencing. Mechanistic investigation was conducted by means of in silico analysis and dual-luciferase reporter gene assay. Tumor xenografts derived from radioresistant EC cells were exposed to local X-ray irradiation in vivo for validation.ResultsHigh expression of HDAC4 was detected in either tumor tissues derived from radiotherapy responders or radioresistant EC cells. Loss of HDAC4 contributed to suppressed proliferation and enhanced apoptosis of radioresistant EC cells. Moreover, our findings revealed that HDAC4 conferred radioresistance of EC by downregulating microRNA-146a (miR-146a). Interleukin-1 receptor-associated kinase 1 (IRAK1) was a target of miR-146a, and its knockdown promoted radiosensitivity. Silencing of HDAC4 radiosensitized EC cells both in vitro and in vivo via the miR-146a/IRAK1 axis.ConclusionHence, loss of HDAC4 upregulated miR-146a to limit radioresistance. This study aids in the better understanding about mechanism responsible for radioresistance of EC.

RMP promotes the proliferation and radioresistance of esophageal carcinoma.

RMP is a RNA polymerase II Subunit RPB-5 associated protein shown to act as an oncogene in several cancer. However, the mechanism of the involvement of RMP in esophageal cancer (EC) remains unclear. We analyzed RMP expression in EC cell lines and EC tissues. The connection between RMP and clinical pathological features of EC was also elucidated. To investigate the role of RMP in EC, We performed CCK-8 assay to evaluate cell proliferation, and Annexin V/PI double-staining to evaluate cell apoptosis. Effect of RMP on tumor progression in nude mouse models was assessed by measurement of volume and weight of tumors. Expression of RMP, CEA and CA199 in vivo were measured by Inmunohistochemical staining. First of all, our study showed that RMP was highly expressed in EC cell lines (compared with normal cells) and tumor tissues (compare with corresponding normal tissues). Then, we found that RMP was bound up with the status of nodal and T stage which indicating that RMP may be related to the growth and malignant degree of EC. Moreover upregulation of RMP could contribute to tumor growth in vitro and vivo. In addition, the results also showed that overexpression of RMP could significantly reduce the susceptibility to radiotherapy. Taken together, all these further suggested that RMP would play a chance-promoting in EC which may provide us a powerful goal for gene targeting treatment of esophageal cancer.

WISP-1 contributes to fractionated irradiation-induced radioresistance in esophageal carcinoma cell lines and mice.

Cancer cells that survive fractionated irradiation can be radioresistant and cause tumor recurrence. However, the molecular mechanisms underlying the development of radioresistance in cancer cells remain elusive. The aim of this study was to investigate the role of WISP-1 in the development of radioresistance in esophageal carcinoma during fractionated irradiation. Radioresistant esophageal cancer cells were generated from normal esophageal cancer cells via fractionated irradiation, and expression levels of related proteins were determined by Western blot. Radiosensitivity of cells was established by clonogenic cell survival assays, and cell cycle distribution was evaluated by flow cytometry. Protein distributions were determined by immunofluorescence, and cell toxicity was evaluated by cell counting kit-8 assays. In vivo validations were performed in a xenograft transplantation mouse model. Our data indicate that WISP-1 plays an important role in the development of radioresistance in esophageal cancer cells during fractionated irradiation. The overexression of WISP-1 in esophageal cancer cells was associated with radioresistance. Depletion of extracellular WISP-1 by antibody neutralizing reversed radioresistance and directly induced mitotic catastrophe resulting in cell death. WISP-1 may be a candidate therapeutic target in the treatment of recurrent esophageal carcinoma after radiotherapy.