Antitumor efficacy of C‐X‐C motif chemokine ligand 14 in hepatocellular carcinoma in vitro and in vivo

Abstract

C-X-C motif chemokine ligand 14 (CXCL14) is a novel gene that is expressed in many normal cells but is absent from or expressed at very low levels in cancerous tissues such as head and neck squamous cell carcinoma (HNSCC), prostate cancer, and pancre-atic cancer. However, the relationship between CXCL14 and hepa-tocellular carcinoma (HCC) remains unclear. Therefore, the exact function of CXCL14, which may modulate antitumor immune responses in certain cancers, was evaluated. CXCL14 was down-regulated in HCC tissues compared to adjacent normal tissues. Moreover, overexpression of CXCL14 had an inhibitory effect on cell proliferation, induced apoptosis and inhibited the invasion of HCC cells in vitro. Upregulation of CXCL14 by lentivirus also significantly suppressed the growth of subcutaneous tumors in nude mice in vivo. We further demonstrated that the loss of CXCL14 expression was regulated by promoter hypermethylation. CXCL14 induced tumor cell apoptosis through both the mitochon-drial and nuclear apoptosis pathways. CXCL14 suppressed tumor cell proliferation through regulation of the cell cycle by down-regulation of cyclins and cyclin-dependent kinases. In conclusion, CXCL14 plays a pivotal role as a potential tumor suppressor in HCC. The re-expression or upregulation of this gene may provide a novel strategy in HCC therapy in the future. (Cancer Sci 2013; 104: 1523-1531) H epatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related deaths worldwide. Eighty-two percent of cases (and deaths) are in developing countries and the death rate is the second highest in China because of the high prevalence of chronic hepatitis B virus infection and liver cirrhosis. (1-3) Japan, unlike other Asian countries, has a high proportion of HCC caused by hepatitis C virus (HCV) infection accounting for 80-90% of all cases. (4) Although there have been many advances in HCC therapy, such as recent target therapies, liver transplantation, proton therapy and interventional radiological treatment, the overall patient outcome has not been improved substantially. The 5-year survival rate is limited to 25-39% after surgery. (5-9) Therefore, novel treatments for liver cancer are urgently needed. (10,11) New treatments such as immuno-therapy and potential novel gene therapy show potential for the treatment of HCC. (12,13) Recent studies have suggested important functions of chemo-kines in various aspects of tumor growth. (14) Chemokines contribute to leukocyte infiltration in tumors, and some chemokines, such as IL-8, CXCL1-3 and CXCL5, also have direct proangiogenic effects. In addition, chemokines, especially the CXC family, are potentially important factors in tumor growth, immunity, invasion, metastasis and potent mediators of neoangiogenesis. (15-17) The chemokine C-X-C motif chemokine ligand 14 (CXCL14), was initially named BRAK because of its isolation from the human breast and kidney-derived cells; however, its function and receptor remain unclear. (18-20) CXCL14 was reported t...

Expression and effect of CXCL14 in colorectal carcinoma

“…FCM analysis indicated that the overexpression of CXCL14 in HR29 cells promoted cell cycle arrest in the G 1 stage. The results of the current study were consistent with the results reported by Wang et al (28) in hepatocellular carcinoma cells.…”

“…Consistent with the results reported by a number of previous tumor-related studies (23)(24)(25)(26)(27)(28), the present study detected that the expression levels of CXCL14 in colorectal carcinoma tissues were significantly lower than those in normal tissues. The current study did contradict the findings of Zeng et al (32), but was consistent with the results of Cao et al (33).…”

“…The identification of CXCL14 led to clinical research into other diseases, including obesity (19,20), bacterial infections (21) and immune system disorders (22,23). In addition to breast cancer tissues, studies have demonstrated low or absent CXCL14 expression in other tissues, including lung cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma and gastric cancer (23)(24)(25)(26)(27)(28). However, in prostate and pancreatic cancer, CXCL14 is generally expressed at a high level (29)(30)(31).…”

The effect of chemokine CC motif ligand 19 on the proliferation and migration of hepatocellular carcinoma

“…Several previous published studies suggested that CXCL14 and CCR6, members of the chemokine family, may serve as potential biomarker and novel molecular Fig. 4 The efficiency of each CCL19-si RNA in HCC cells target in cancer therapy for HCC [9,10]. Chemokines and chemokine receptors not only have significant roles in cancer metastasis and tumorigenesis but also act as anti-tumor agents.…”

Expression and Clinical Significance of the Novel Long Noncoding RNA ZNF674-AS1 in Human Hepatocellular Carcinoma

“…The cycling conditions were as follows: denaturation at 94°C for 5 min, followed by 40 cycles of 95°C for 30 s, 58°C for 30 s, and 72°C for 20 s. All of the experiments were conducted three times, and the average was determined. The 2 −ΔΔCt formula was used to calculate differential gene expression [19]. …”