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Tenascin-C induces resistance to apoptosis in pancreatic cancer cell through activation of ERK/NF-κB pathway

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Abstract

As a glycol-protein located in extracellular matrix (ECM), tenascin-C (TNC) is absent in most normal adult tissues but is highly expressed in the majority of malignant solid tumors. Pancreatic cancer is characterized by an abundant fibrous tissue rich in TNC. Although it was reported that TNC’s expression increased in the progression from low-grade precursor lesions to invasive cancer and was associated with tumor differentiation in human pancreatic cancer, studies on the relations between TNC and tumor progression in pancreatic cancer were rare. In this study, we performed an analysis to determine the effects of TNC on modulating cell apoptosis and chemo-resistance and explored its mechanisms involving activation in pancreatic cancer cell. The expressions of TNC, ERK1/2/p-ERK1/2, Bcl-xL and Bcl-2 were detected by immunohistochemistry and western blotting. Then the effects of exogenous and endogenous TNC on the regulation of tumor proliferation, apoptosis and gemcitabine cytotoxicity were investigated. The associations among the TNC knockdown, TNC stimulation and expressions of ERK1/2/NF-κB/p65 and apoptotic regulatory proteins were also analyzed in cell lines. The mechanism of TNC on modulating cancer cell apoptosis and drug resistant through activation of ERK1/2/NF-κB/p65 signals was evaluated. The effect of TNC on regulating cell cycle distribution was also tested. TNC, ERK1/2/p-ERK1/2, and apoptotic regulatory proteins Bcl-xL and Bcl-2 were highly expressed in human pancreatic cancer tissues. In vitro, exogenous TNC promoted pancreatic cancer cell growth also mediates basal as well as starved and drug-induced apoptosis in pancreatic cancer cells. The effects of TNC on anti-apoptosis were induced by the activation state of ERK1/2/NF-κB/p65 signals in pancreatic cell. TNC phosphorylate ERK1/2 to induce NF-κB/p65 nucleus translocation. The latter contributes to promote Bcl-xL, Bcl-2 protein expressions and reduce caspase activity, which inhibit cell apoptotic processes. TNC mediated gemcitabine chemo-resistance via modulating cell apoptosis in pancreatic cancer. TNC resulted in the enrichment of pancreatic cancer cells in S-phase with a concomitant decrease in number of cells in G1 phase. The present study indicated TNC in cellular matrix induces an activation of ERK1/2/NF-κB/p65 signaling cascade and thereby mediates resistance to apoptosis in pancreatic cancer. TNC could serve as a diagnostic marker and predictor of gemcitabine response and potentially as a target for chemotherapy of pancreatic cancer.

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Acknowledgments

This study was funded by National Natural Fund (31370861) and Tianjin Basic Research Plan Project (13JCZDJC31300). The authors declare that they have no conflict of interest. We thank Tianjin Medical University Cancer Institute and Hospital for providing human pancreatic adenocarcinoma samples and for all expert discussions. We thank Dwayne Stupack (University of California, San Diego, USA) for giving helpful advice during the course of our study.

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Authors and Affiliations

  1. School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China

    Meiyan Shi, Xiaodan He, Juan Wang & Xiaohong Shen

  2. Tianjin Medical University Cancer Institute and Hospital, Huanhu West Road, Tianjin, 300060, China

    Wei Wei & Ti Zhang

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  1. Meiyan Shi
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  2. Xiaodan He
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  3. Wei Wei
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Correspondence to Xiaohong Shen.

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Shi, M., He, X., Wei, W. et al. Tenascin-C induces resistance to apoptosis in pancreatic cancer cell through activation of ERK/NF-κB pathway. Apoptosis 20, 843–857 (2015). https://doi.org/10.1007/s10495-015-1106-4

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