COMMD7 promotes hepatocellular carcinoma through regulating CXCL10
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.
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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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