Resistance to radiotherapy results in relapse and treatment failure in locally advanced esophageal squamous cell carcinoma (ESCC). High mobility group box 1 (HMGB1) is reported to be associated with the radioresistance in bladder and breast cancer. However, the role of HMGB1 in the radiotherapy response in ESCC has not been fully elucidated. Here, we investigated the role of HMGB1 to radioresistance in ESCC clinical samples and cell lines. We found that HMGB1 expression was associated with tumor recurrence after postoperative radiotherapy in locally advanced ESCC patients. HMGB1 knockdown in ESCC cells resulted in increased radiosensitivity both in vitro and in vivo. Autophagy level was found depressed in HMGB1 inhibition cells and activation of autophagy brought back cell’s radioresistance. Our results demonstrate that HMGB1 activate autophagy and consequently promote radioresistance. HMGB1 may be used as a predictor of poor response to radiotherapy in ESCC patients. Our finding also highlights the importance of the utility of HMGB1 in ESCC radiosensitization.
High-risk human papillomavirus (HPV), especially HPV16, correlates with cancerogenesis of human esophageal squamous cell carcinoma (ESCC) and we have reported that HPV16 related with a poor prognosis of ESCC patients in China. We aim to investigate the potential role and mechanism of HPV16 in ESCC development and progress. Our following researches demonstrated that ESCC cells which were stably transfected by HPV16 E6-E7 lentiviral vector showed a remarkable cancer stem-like cells (CSCs) phenotype, such as: migration, invasion, spherogenesis, high expression of CSCs marker in ESCC---p75NTR, chemoresistance, radioresistance, anti-apoptosis ability in vitro and cancerogenesis in vivo. HPV16 E6-E7 induced PI3K/Akt signaling pathway activation and this affect could be effectively inhibited by LY294002, a specific PI3K inhibitor. It was also indicated that the inhibition of PI3K/Akt signaling pathway by PI3K and Akt siRNA reverse the effect which induced by HPV16 E6-E7 in ESCC cells. Taken together, the present study demonstrates that HPV16 E6-E7 promotes CSCs phenotype in ESCC cells through the activation of PI3K/Akt signaling pathway. Targeting the PI3K/Akt signaling pathway in HPV16 positive tissues is an available therapeutic for ESCC patients.
BackgroundGastric cancer (GC) is one of the most commonly occuring gastrointestinal tumor types, and early diagnosis and operation have a notable effect on the prognosis of patients. Although certain markers, including HER2, VEGER-2, ERCC1 and Bcl-2, have been utilized in clinical practise to screen out new patients with GC, the results of using these markers remains poor. The role of olfactomedin-like 2B (OLFML2B) in GC, as a member of the olfactomedin domain-containing proteins family, is remain unclear.MethodsIn the present study, we assessed the expression of OLFML2B, including mRNA and protein level, by using The Cancer Genome Atlas (TCGA) database and 13 pairs of clinical samples between GC and NG tissues. The correlation between expression of OLFML2B and prognosis of GC was evaculated by the Kaplan-Meier plotter and OncoLnc online tools. In addition, mechanism analysis of OLFML2B in GC was explored thought bioinformatic tools, including cBioPortal and FunRich software.ResultsIn our study, the mRNA expression of OLFML2B in GC both TCGA database and clinical samples was consistently revealed to be significantly higher compared with that in NG tissues (P < 0.0001 for TCGA database and P = 0.0034 for clinical samples), and high OLFML2B expression was found in 9 (69.23%) of 13 clinical GC by immunohistochemistry and was positively correlated with the depth of tumor invasion and clinical stage (TNM). In addition, the AUC for a ROC of 0.867 indicated a moderate diagnostic ability of OLFML2B for GC. Survival analysis from the Kaplan-Meier plotter (P = 2.6 × 10− 6) and OncoLnc (P = 0.00276) revealed that the high expression of OLFML2B was associated with a short overall survival. Futhermore, 5% (24/478) alterations of OLFML2B were identified from cBioPortal, and among them, missense mutation (14/478) was the primary type. The results from FunRich revealed that OLFML2B participated in mediating multiple biological processes including cell growth and maintenance, regulation of the cell cycle, apoptosis and cell communication through multiple signaling pathways including the M/G1 transition pathway, post-translational protein modification and DNA replication pre-initiation.ConclusionsTaken together, it could be deduced that OLFML2B may act as an oncogene in the development of GC and the overexpression of OLFML2B in GC may be used as a novel diagnostic and prognostic target for GC.
Radiation therapy is one of the most important treatments for unresectable and locally advanced esophageal squamous cell carcinoma (ESCC), however, the response to radiotherapy is sometimes limited by the development of radioresistance. Sinomenine hydrochloride (SH) has anticancer activity, but its effect on the radiosensitivity of ESCC is unclear. We determined the effect of SH on the radiosensitivity of ESCC cells and elucidated its potential radiosensitization mechanisms in vitro and in vivo. ESCC cells were subjected to SH and radiation, both separately and in combination. Untreated cells served as controls. The CCK-8 assay was used to evaluate cell proliferation, and the clonogenic assay to estimate radiosensitization. Flow cytometry was used to investigate cell cycle phases and cell apoptosis. Bcl-2, Bax, cyclin B1, CDK1, Ku86, Ku70, and Rad51 expression was evaluated using western blotting. In vivo, tumor xenografts were created using BALB/c nude mice. Tumor-growth inhibition was recorded, and Ki-67 and Bax expression in the tumor tissues was assessed using immunohistochemistry. SH inhibited ESCC cell growth and markedly increased their radiosensitivity by inducing G2/M phase arrest. SH combined with radiation therapy significantly increased ESCC cell apoptosis. The molecular mechanism by which SH enhanced radiosensitivity of ESCC cells was related to Bcl-2, cyclin B1, CDK1, Ku86, Ku70, and Rad51 downregulation and Bax protein expression upregulation. SH combined with radiation considerably delayed the growth of tumor xenografts in vivo. Immunohistochemical analysis showed that in the SH combined with radiation group, the expression of Bax was significantly higher while that of Ki-67 was lower than the expressions in the control groups. Taken together, our findings showed that SH could improve the sensitivity of radiation in ESCC cells by inducing G2/M phase arrest, promoting radiation-induced apoptosis and inhibiting DSB-repair pathways. SH appears to be a prospective radiosensitizer for improving the efficacy of radiotherapy for ESCC.
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