Abstract
BackgroundRadiotherapy is a major treatment for esophageal squamous cell carcinoma (ESCC). However, HPV infection related radioresistance caused poor prognosis of ESCC. The function of SOCS6, which has been shown to be a tumor suppressor in several cancers, has not been fully investigated up till now. In this manuscript, we aim to further investigate the role of SOCS6 in regulating ESCC radioresistance.MethodsFifty-seven ESCC patients were enrolled for survival analysis. SOCS6 was stably overexpressed in HPV+ ESCC and ESCC cells, and cells were treated with radiation and then subjected to colony formation assays. Expression of DNA damage repair regulating proteins were examined by Western blotting. Cell growth, cell migration and cisplatin sensitivity were then analyzed. Sphere formation assays and flow cytometry were used to investigate changes in cancer stem cell (CSC) properties. Immunofluorescent staining and confocal microscopy were used to locate SOCS6 and c-Kit. Ubiquitylation level of c-Kit were analyzed after immunoprecipitation. Then, coimmunoprecipitation (CoIP) of SOCS6 and c-Kit were performed. In vivo, xenograft animal models were treated with radiation to examine the radiosensitivity.ResultsSOCS6 is correlated with better prognosis in ESCC patients. Radioresistance is impaired by SOCS6 upregulation, which inhibited cell growth, migration and increased sensitivity to cisplatin. SOCS6 significantly decreased the population of CSCs expressing the surface biomarker CD271 or CD24low/CD44high and their ability of sphere formation. SOCS6 and c-Kit were collocated in the cytoplasm. Blotting of ubiquitin and CoIP experiments indicated that the mechanism was related to ubiquitylation and degradation of the receptor c-Kit. Xenograft tumor mouse model showed that SOCS6 inhibited tumor growth and promoted radiosensitivity in vivo.ConclusionsOur findings suggest that SOCS6 can promote the radiosensitivity of HPV+ ESCC and ESCC cells and reduce their stemness via ubiquitylation and degradation of c-Kit. Thus, SOCS6 is a potential target for overcoming radioresistance of ESCC.
Highlights
Radiotherapy is a major treatment for esophageal squamous cell carcinoma (ESCC)
We previously reported that downregulation of SOCS6 via ceRNA mechanism increased cell growth of ESCC and that human papillomavirus (HPV) infection increased the proportion of Cancer stem cells (CSCs) in ESCC cells, which induced radioresistance [37, 38]
Since low expression of SOCS6 is correlated with poor prognosis in ESCC patients, we suspected that SOCS6 is a negative regulator of ESCC and that SOCS6 might promote radiosensitivity
Summary
Radiotherapy is a major treatment for esophageal squamous cell carcinoma (ESCC). HPV infection related radioresistance caused poor prognosis of ESCC. The function of SOCS6, which has been shown to be a tumor suppressor in several cancers, has not been fully investigated up till now. The function of SOCS6, which has been shown to be a tumor suppressor in several cancers, has not been fully investigated up till In this manuscript, we aim to further investigate the role of SOCS6 in regulating ESCC radioresistance. SOCS6 was stably overexpressed in H PV+ ESCC and ESCC cells, and cells were treated with radiation and subjected to colony formation assays. HPV is a major prognostic factor in head and neck squamous cell carcinoma (HNSCC) and cervical cancer [5]. In ESCC, our previous study found that HPV is a negative prognostic factor and that HPV attenuates the radiosensitivity of ESCC cells [7]
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