| BACKGROUND Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer and the third most common leading cause of cancer-related death worldwide, and the burden of this devastating cancer is expected to increase in coming years. The majority patients are diagnosed at advanced stage and thus not in a position for curative treatments, which have very limited options, and the only systemic therapy currently approved is sorafenib, an oral tyrosine kinase inhibitor drug targeting multiple signalling pathways. The objective response rate (ORR), however, was poor. HCC is considered a poor responder to chemotherapy and a standard systemic treatment does not exist for patients for whom sorafenib is unsuitable or unavailable. The reason could be the frequently observed development of multidrug tumor resistance, which is related to the high expression of the multidrug-resistance gene. The progression of cancer is no longer recognized as an independent event which only relates to the genetic mutation and uncontrollable growth of cancer cells. New therapeutic strategies are urgently needed, and these will most likely result from a better understanding of the cell biology of HCC.The interaction between tumor cells and their microenvironment has been recognized to fundamentally affect tumor progression. Physiologically, the surrounding microenvironment constitutes an important barrier to cell transformation and notably modulate cell growth. Under cancer conditions, the tumor microenvironment experiences drastic changes including the recruitment and the activation of stromal cells and the remodeling of extracellular matrix (ECM), may influence the phenotype of tumor cells and provide a selective pressure for tumor initiation, progression and metastasis.The remodeling of tumor microenvironment is one of the hallmarks of HCC pathogenesis. The majority of HCC patients have an established background of chronic liver disease, and the presence of liver cirrhosis is the main risk factor for the development of HCC. In addition, HCC is the leading cause of death among patients with cirrhosis. Hepatic stellate cells (HSCs), the versatile mesenchymal cells in the liver parenchyma, are vital to the liver’s response to inflammation. Activation of HSCs is recognized as a central event in the development of hepatic fibrosis and subsequent, cirrhosis. In response to liver injury, quiescent HSCs become activated and convert into highly proliferative myofibroblast-like cells, which express inflammatory and fibrogenic mediators responsible for ECM accumulation within the microenvironment, and may affect proliferation, invasiveness and metastasis of tumor cells, and facilitates hepatic tumorigenesis. However, the detailed mechanisms responsible for these effects remain unclear.Tumor mass is a balance between cell proliferation and death, and factors affecting this balance have a profound effect on tumor growth. Regulation of apoptosis in tumor cells remains poorly understood. Furthermore, few studies demonstrate the effects of HSCs on HCC from the chemotherapy-resistance perspective.AIM The aim of our study here was determine if HSCs could provide a survival signal, or block a death signal, thereby accounting for the protection of HCC cells from chemotherapy induced apoptosis.METHODS HepG2cells were treated with cisplatin alone or co-cultured with LX-2cells3days before incubation with cisplatin. Hoechst33258staining was used to detect cell viability. Cell cycle was detected by flow cytometry. Annexin-V-FITC/PI double staining assay was used to detect cellular apoptosis. Cellular morphological changes were observed under an inverted phase contrast microscope. Expression levels of p53, Bax and Bcl-2mRNA were measured by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Expression levels of Bax and Bcl-2protein were measured by Western blot analysis.RESULTS Cisplatin causes apoptosis in HepG2cells. and LX-2cells protects HepG2cells from death. The protective effects of LX-2cells against cisplatin-induced cytotoxicity in HepG2appeared to be related to the inhibition of apoptosis, as determined by cytotoxicity assay, nuclear staining analysis and Annexin-V-FITC/PI staining assay. p53and Bax mRNA levels were elevated, and cell cycle arrest was produced after cisplatin treatment. LX-2cells suppressed this elevation of p53and Bax as well as the cell cycle arrest induced by cisplatin, when compared with those of the treated cells with cisplatin alone. The LX-2cells pretreatment inhibited the cisplatin-induced apoptosis, which was related with the incomplete blockage in p53activation.CONCLUSIONS The results of our present study demonstrate that HSCs protect HepG2cells against cisplatin-induced apoptosis and its protective effects occur via inhibiting the activation of p53, which is of critical importance for enhanced understanding of fundamental cancer biology. |
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