TAZ-regulated expression of IL-8 is involved in chemoresistance of hepatocellular carcinoma cells

Highlights

• TAZ was upregulated in chemoresistant HCC cells.

• Inhibition of TAZ can restore chemosensitivity of HCC cells.

• IL-8 mediated TAZ-regulated chemosensitivity of HCC cells.

• TAZ can bind with IL-8 promoter to activate its transcription.

Abstract

Chemotherapy resistance is one of the major challenges for the treatment of hepatocellular carcinoma (HCC). In order to investigate the mechanisms involved in chemoresistance of HCC, we established cisplatin (CDDP) and doxorubicin (Dox) resistant HCC cells. The expression of transcriptional coactivator with PDZ-binding motif (TAZ), one of the major downstream effectors of Hippo pathway, was upregulated in chemoresistant HCC cells. Targeted inhibition of TAZ via its siRNAs can restore CDDP and Dox sensitivity of chemoresistant HCC cells. The upregulation of TAZ increased the expression of IL-8 in HCC/CDDP and HCC/Dox cells. Recombinant IL-8 (rIL-8) antagonized the increased chemosensitivity mediated by TAZ knockdown. Mechanistically, TAZ can directly bind with the promoter of IL-8 to activate its transcription in chemoresistant HCC cells. Collectively, our data showed that TAZ-regulated expression of IL-8 was involved in chemoresistance of HCC cells. It indicated that targeted inhibition of TAZ/IL-8 axis might be helpful to improve chemotherapy efficiency for HCC.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide [25]. In China, HCC has become the second leading cause of cancer-related death in men [25]. The liver resection or transplantation have been used to treat early-stage HCC. As for HCC patients at advanced stages, chemotherapy or radiotherapy may improve the survival of patients [17]. Although recent advances in HCC therapy, there are still poor prognosis and high recurrence rate for cancer patients. The acquired drug resistance is one of the major obstacles for HCC chemotherapy [3]. It has been reported that only 20% of HCC patients can effectively response to chemotherapy [20]. Therefore, it is crucial important to understand mechanisms responsible for chemoresistance of HCC, in order to seek novel treatment strategies to improve therapy efficiency.

Multiple mechanisms such as gene mutation, metabolic reprogramming, DNA methylation, and histone modification are involved in chemoresistance of cancer cells [2]. Among these mechanisms, the abnormal activation of oncogenic pathway is a major cause of acquired resistance in cancer [16]. The dysregulation of Hippo pathway can regulate development of various cancers [28]. As the core component of Hippo pathway, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) correlated with the poor prognosis of cancer progression [[36], [37], [38]] and might be involved in chemoresistance [19]. For example, TAZ can maintain 5-FU resistance of colon cancer cells by regulation of Cyclin E1 and CREB [7]. A TAZ-ANGPTL4-NOX2 axis can regulate chemoresistance of epithelial ovarian cancer [34]. TAZ is required for chemoresistance and tumorigenic potential of breast cancer cells [4]. Previous studies indicated that TAZ can induce proliferation and migration of cancer cells and act as the candidate oncogene in HCC [8,32], but its roles in chemosensitivity of HCC cells were not illustrated.

It has been reported that cytokines such as interleukins and transforming growth factor-β (TGF-β) are critical for the development of HCC, further, they can confer resistance of cancer cells to chemotherapy [35]. Our present study showed that TAZ was increased in HCC chemoresistant cells. Further, it can regulate chemosensitivity of HCC cells via regulation of IL-8. All these data suggested that TAZ/IL-8 signals might be the potential target to overcome chemoresistance of HCC cells.