Increased HMGB1 and cleaved caspase-3 stimulate the proliferation of tumor cells and are correlated with the poor prognosis in colorectal cancer.

Zhengxiang Zhang,Ying Zhu,Yang Yu,Xiao Feng,Chuanyuan Li,Yanping Gong,Min Wang,Ling Zhou,Qian Huang,Jin Cheng,Ling Tian

doi:10.1186/s13046-015-0166-1

Abstract

BackgroundDying tumor cells after irradiation could promote the proliferation of living tumor cells might cause tumor relapse and treatment failure. Our previous study showed that activated caspase-3 after irradiation probably participates in tumor repopulation. In this study, we investigated whether high mobility group box 1(HMGB1) is also involved in tumor repopulation.MethodsColorectal tumor cells were irradiated. The cleaved caspase-3 (CC3) in irradiated tumor cells and HMGB1 in the supernatant of irradiated tumor cells were detected by Western blot. A large number of irradiated colorectal tumor cells (feeder cells) were then co-cultured with a small number of luciferase-labeled living colorectal tumor cells (reporter cells) and proliferation of reporter cells was measured by bioluminescence imaging. The CC3 and HMGB1 protein expression in colorectal tumor and peritumoral tissues were detected by immunohistochemistry and their correlation with prognosis were analyzed.ResultsThe irradiated colorectal tumor cells underwent apoptosis and necrosis and produced CC3 in tumor cells and HMGB1 in the supernatant of cultured cells. The increased expression of secretory HMGB1 correlated with CC3 level and proliferating cell nuclear antigen (PCNA) after irradiation in vitro. The irradiated dying cells remarkably stimulated living tumor cell proliferation. Interestedly, immunohistochemistry staining showed that positive HMGB1, CC3, and Ki67 expression were significantly higher in colorectal tumor tissues than in peritumoral tissues (p <0.01). The Kaplan-Meier survival analysis revealed that high HMGB1, CC3, and Ki67 levels were significantly associated with poor prognosis (p <0.05, p <0.01). Multivariate analysis using Cox proportional hazards model showed that TNM staging and HMGB1 were independent prognostic factors in patients with colorectal cancer (CRC) (p <0.01, p <0.001).ConclusionBoth apoptotic and necrotic cells could stimulate proliferation of living tumor cells, and the increased expression of CC3 and HMGB1 in tumor cells could be new markers for poor prognosis in colorectal cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0166-1) contains supplementary material, which is available to authorized users.

Highlights

Resistance to chemotherapy and radiotherapy is a universal obstacle in cancer treatment and one of the main causes of tumor relapse and treatment failure
Cell culture and irradiation HT29, HCT8, SW620, CaCO2, RKO cells were purchased from the Chinese Academy of Science (Shanghai, China) and cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) (Thermo Scientific Inc., Beijing, China) containing 10 % fetal bovine serum (FBS) (Tianhang Biological Technology Co., Ltd., Hangzhou, China), supplemented with 1 % penicillin and 1 % streptomycin at 37 °C under 5 % CO2
Multivariate analysis using Cox proportional hazards model showed that TNM staging and High mobility group box 1 (HMGB1) (p = 0.000 and p = 0.008, respectively), but not cleaved caspase-3 (CC3) and Ki67 (p = 0.998 and p = 0.347, respectively) were independent prognostic factors in colorectal cancer (CRC) patients (Table 4)

Summary

Introduction

Resistance to chemotherapy and radiotherapy is a universal obstacle in cancer treatment and one of the main causes of tumor relapse and treatment failure. A recent study of ours demonstrated that dying tumor cells after radiotherapy can stimulate the proliferation of residual living tumor cells, which may be a possible mechanism of tumor resistance and repopulation after radiotherapy [2]. This process was found to be associated with the activation of caspase and caspase-7. A recent study by Kurtova et al demonstrated that chemotherapy effectively induces apoptosis and PGE2 release, which paradoxically promotes neighboring cancer stem cell repopulation and leads to subsequent chemoresistance [4]. Dying tumor cells after irradiation could promote the proliferation of living tumor cells might cause tumor relapse and treatment failure. We investigated whether high mobility group box 1(HMGB1) is involved in tumor repopulation

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Results

Conclusion