WITHDRAWN: Hepatic stellate cells transmigration and remodeling are related to CCN3 in oxaliplatin-resistant hepatocellular carcinoma

Abstract

// Ruitao Wang 1 , Wei Cheng 2 , Zhen Wang 2 , Qiangbo Zhang 3 , Yang Bu 4 , Songning Yu 4 and Qingan Jia 1 1 Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China 2 Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University Health Center, Xi’an 710061, China 3 Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China 4 Department of Hepatobiliary Surgery, General Hospital, Ningxia Medical University, Yinchuan 750001, China Correspondence to: Qingan Jia, email: qajia66@163.com Keywords: hepatocellular carcinoma; CCN3; hepatic stellate cells; microenvironment; oxaliplatin resistance Received: October 31, 2017      Accepted: December 05, 2017      Published: January 13, 2018 ABSTRACT Background: Hepatic stellate cells (HSCs) have a key role in fibrogenesis and in the filtrates of the hepatocellular carcinoma (HCC) stroma, in which they are remodeled and play a critical role in HCC progression. While, the precise mechanism associated with HSCs trending, infiltration and remodeling is still vague in HCC, especially in Oxaliplatin-resistant HCC. Materials and Methods: The chemoresistant cell and mouse model, and the HCC clinical samples were collected and were established. We explored the relationship between secretory CCN3 from Oxaliplatin-resistant HCC and the infiltration of HSCs in Oxaliplatin-resistant HCC microenvironment. We also evaluated the associated mechanism of HSCs infiltration and HSCs remodeling in HCC with high expression of CCN3. Results: We constructed oxaliplatin-resistant HCC models and found the increased infiltration of HSCs into the microenvironment. We reanalyzed the cDNA profiles of the oxaliplatin-resistant HCC and found CCN3 was one of the significantly increased genes. In HCC clinical samples, the levels of CCN3 and α-SMA are positively correlated, and high expression of CCN3 and α-SMA are positively associated with malignant phenotype and poor prognosis. Then we proved that CCN3 could enhance the migration and proliferation of HSC, and induce the remodeling of HSC with elevation of cytokines relating to HCC malignancy, which was related to ERK signaling pathway activation. Finally, we confirmed that the role of CCN3 enhanced the transmigration of HSCs using the xenograft tumor model. Conclusions: HSCs transmigration and remodeling are positively related to CCN3 paracrine in hepatocellular carcinoma, which orchestrated the stroma-derived resistance to chemotherapy in HCC.