Elsevier

Biomedicine & Pharmacotherapy

Volume 88, April 2017, Pages 653-657
Biomedicine & Pharmacotherapy

COMMD7 promotes hepatocellular carcinoma through regulating CXCL10

https://doi.org/10.1016/j.biopha.2017.01.046Get rights and content

Abstract

Hepatocellular carcinoma (HCC) is still a heavy threat to public health. However, novel therapeutic and diagnostic method for HCC is still urgently needed thus far. Based on sequence analysis and homology comparison, we previously reported a novel gene termed COMMD7, which is mapped to 20q11.22 and promotes cell proliferation in HCC cells. But the molecular mechanisms underlying the pro-tumor property of COMMD7 are not fully addressed yet. In this study, we demonstrate that the conditional medium derived from COMMD7-overexpressed HCC cell promotes proliferation of naïve HCC cells. The over-expression of COMMD7 significantly induced the migratory and invasive in HCC cells. Mechanistic study found that over-expression of COMMD7 induces C-X-C motif chemokine 10 (CXCL10) expression. Blocking CXCL10 signal transduction by neutralizing antibody abolished COMMD7-mediated cell proliferation and migration. In conclusion, COMMD7 promotes hepatocellular carcinoma through regulating CXCL10. The present data suggests a potential role of CXCL10 in the oncogenic function of COMMD7, and will lead to a better understanding of the development of HCC.

Introduction

To date, hepatocellular carcinoma (HCC) is still a heavy threat to public health, representing the fifth most prevalent malignancy worldwide and causing 600 000 deaths annually [1]. Surgical resection coupled with chemotherapy and liver transplantation is currently the routing treatment for HCC patients. However, these curative methods are only available to patients with limited disease, which represent only one third of the total HCC patients [2]. Moreover, the risk of metastasis/recurrence is still high for those patients who received surgical resection [3]. Therefore, novel therapeutic and diagnostic method for HCC is still urgently needed thus far.

As other tumor types, development of HCC includes multi-step processes, initially with pre-malignant lesions, hyperplasia to dysplasia, then carcinoma in situ, and finally tumor cell dissemination to distant organ [4]. These steps could be characterized by wide variety of molecular events, such as mutation, abnormal expression or abnormalities in translation, modification and sub-cellular location of a cluster of oncogenes or tumor suppressor genes [5]. Therefore, for years, global genomic or proteomic profiling, such DNA micro-array or 2-DE-based approaches, have been used as a powerful tool to explore the molecular changes associated with HCC tumorigenesis [6]. However, though a large volume of data on biomarkers or therapeutic targets has been documented, the prognosis of HCC remains poor, which suggests a persistent need for a detailed identification of novel factors involved in HCC tumorigenesis [7].

In our previous work, a novel cDNA fragment was found to be over-expressed in HCC clinical samples by suppression subtractive hybridization. Based on sequence analysis and homology comparison, we confirmed that this cDNA fragment was derived from COMMD7 gene mapped to 20q11.22. Further, shRNA-mediated COMMD7 knockdown suppressed HCC cell proliferation, suggesting a positive regulatory role of COMMD7 on HCC [8]. However, the precise mechanisms underlying the impact of COMMD7 on HCC cell proliferation was still unclear. In this study, we demonstrate that COMMD7 promoted HCC cell line proliferation by inducing CXCL10 production.

Section snippets

Cell lines

Human HCC cancer cell line Hep3B, HepG2, HLE and Huh7 were purchased from American Type Culture Collection (ATCC, Rockville, MD, USA). All the cell lines were maintained in Dulbecco’s Modified Eagle’s Medium (Invitrogen, USA) containing 10% fetal calf serum (Hyclone, Logan, UT, USA), penicillin (107 U/L) and streptomycin (10 mg/L) at 37 °C in a humidified chamber containing 5% CO2.

Reagents

COMMD7 and Neut CXCL10 antibodies were purchased from Abcam. EGF, HGF, IL2, IL4 and TNF-α ELISA kit were purchased

Conditional media from COMMD7-expressed HCC cells promotes proliferation and metastasis in normal HCC cells

To determine the molecular mechanism responsible for COMMD7-induced HCC cell line proliferation, we exogenously expressed COMMD7 in Huh7 cell line, since our previous findings showed that COMMD7 expression was relatively low in Huh7 cell line compared to other HCC cell lines. As shown in Fig. 1A, transfection of expression vector coding full length COMMD7 markedly augmented COMMD7 expression in Huh7 cell line compared to mock vector treated cells. Similar with our previous report,

Discussion

HCC has been among the most common life-threatening malignancies worldwide for decades, and, even nowadays, it is still a major problem in public health [11]. Development of HCC is a multiple-step process, and results from complicated interconnections between genetic and environmental factors which regulate cell cycle, immune evasion, energy metabolism and cell-cell adhesive contacts [12]. Thus a more detailed identification of the key molecules involved in HCC development must be amenable to

Conclusions

In present data, we showed that the level of CXCL10 expression was positively associated with COMMD7 in primary hepatocytes and a panel of HCC cell lines. Further, modulation of COMMD7 expression altered CXCL10 expression in HCC cells. More importantly, interference of CXCL10 signaling transduction significantly abolished the pro-proliferative and pro-metastatic property of COMMD7. To further support our findings, more work is still needed to determine the relationship of CXCL10 and COMMD7 by

Conflict of interest

Authors declare that they have no competing interests.

Acknowledgement

This study was granted by the National Natural Science Fund (Grant No. NSFC 81372561).

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