CKLF1 Enhances Inflammation-Mediated Carcinogenesis and Prevents Doxorubicin-Induced Apoptosis via IL6/STAT3 Signaling in HCC

Abstract

Purpose: Hepatocellular carcinoma (HCC), one of the most common and deadliest malignancies worldwide, has a poor prognosis, owing to its high potential for vascular invasion and metastasis and the lack of biomarkers for early diagnosis. Thus, it must be a crucial factor for investigating therapeutic strategies for HCC to identify the functional molecular targets. Here, we reported a novel chemokine, CKLF1, that might act as a pivotal modulator in the invasion and metastasis of HCC and could serve as an attractive target for cancer therapy.Experimental Design: Bioinformatics analysis, PCR, Western blotting, and IHC were performed to detect the expression of CKLF1 in HCC. The function of CKLF1 was demonstrated by a series of in vitro and in vivo experiments. Pharmacologic treatment, flow cytometry, and Western blotting were carried out to demonstrate the potential mechanisms of CKLF1.Results: We proved that CKLF1 was overexpressed in HCC tissues and was related to tumor stage, vascular invasion, and patient survival. Then, functional assays showed that CKLF1 promoted hepatocellular carcinogenesis and metastatic potential. Finally, the IL6/STAT3 signaling pathway was involved in the mechanistic investigation. The results demonstrated that CKLF1 enhanced the progression of HCC and prevented doxorubicin-induced apoptosis through activating the IL6/ STAT3 pathway.Conclusions: These data showed that CKLF1 inhibited apoptosis and promoted malignant transformation through the IL6/STAT3 pathway, and ultimately enhanced the development and metastasis of HCC. Thus, our work revealed that CKLF1 was a significant prognostic factor of HCC and might be a potential molecular therapeutic target for HCC.

Chemokine-like factor 1: A promising therapeutic target in human diseases

“…33 Recently, a research found that the expression level of CKLF1 was much higher in cancerous tissues than that in non-cancer tissues from patients with liver hepatocellular carcinoma (LIHC), and CKLF1 was more highly expressed in advanced tumors than in low-stage tumors. 34 Here we confirmed that CKLF1 was up-regulated in LIHC patients, based on large-scale RNA_Seq data from TCGA (Figure 2 (a)). 35 Excepting tumor staging, CKLF1 was also shown to be associated with vascular invasion, and patient survival.…”

Targeting macrophage priming by polyphyllin VII triggers anti-tumor immunity via STING-governed cytotoxic T-cell infiltration in lung cancer

“…7c,d). Since IL-6/STAT3/IL-10/TGF-β plays pivotal role in carcinogenesis and EMT [39][40][41][42][43][45][46][47][48] , to verify whether this axis is involved in malignant transformation of tumor cells regulated by transformed macrophage-CMs, we detected the changes of several major indicators in this process. The expression of Vimentin (an indicator of EMT) and PCNA (related to active proliferation) was in line with the trend of STAT3 phosphorylation regulated by STING in response to PP VII.…”

Increased expression of hematological and neurological expressed 1 (HN1) is associated with a poor prognosis of hepatocellular carcinoma and its knockdown inhibits cell growth and migration partly by down‐regulation of c‐Met

“…Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, and its incidence has been increasing in recent years . Although great progress has been made in the diagnosis and treatment of HCC, the 5‐year overall survival rate for HCC patients is still very low .…”