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Abstract
Inflammatory factors and activation of oncogenes both played critical roles in the development and progression of human hepatocellular carcinoma (HCC). However, the interplay between these two has not been well studied. In this study, we found that regulated by TNFα, Pim-2 proto-oncogene, serine/threonine kinase (PIM2) was highly expressed in HCC and correlated with poor prognosis (P = 0.007) as well as tumor recurrence (P = 0.014). Functional studies showed that PIM2 could enhance abilities of cell proliferation, cell motility, angiogenesis, chemo-resistance, and in vivo tumorigenicity and HCC metastasis. Mechanistic studies revealed that PIM2 could activate NF-κB signaling pathway through upregulating phosphorylation level of RIPK2. Interestingly, TNFα treatment could induce the expression of PIM2, and overexpression of PIM2 could in turn upregulate the expression of TNFα in HCC cells. More importantly, we found the expression level of PIM2 increased with the progression of liver cirrhosis, and PIM kinase inhibitor AZD1208 treatment could effectively attenuate HCC cells’ tumorigenic ability both in vitro and in vivo. Collectively, our study revealed the interaction between an inflammatory factor and a proto-oncogene that contributed to tumorigenesis and progression of HCC, and PIM kinase inhibition may serve as a therapeutic target in the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common human malignancies as well as one of the leading causes of cancer related mortality worldwide[1]
Clinical significance of PIM2 upregulation in HCC patients To analyze the association of PIM2 upregulation with clinicopathological features in 134 HCC patients, HCC patients were divided into two groups with twofold increase as the cut-off line
Scale bar stands for 20 μm. e Relative expression level of RIPK2 in empty vector-transduced and PIM2-transduced 7703 and 7402 cells detected by qRT-PCR, and expression of RIPK2 and p-RIPK2 in empty vector-transduced and PIM2-transduced HCC cells detected by Western Blot
Summary
Hepatocellular carcinoma (HCC) is one of the most common human malignancies as well as one of the leading causes of cancer related mortality worldwide[1]. Major risk factors for HCC development, include chronic infection of hepatitis B/C viruses, alcohol consumption, and aflatoxin intake[2]. The close association between HCC and chronic hepatitis is well established according to etiological studies, and approximately 80% HCC patients have hepatitis history[3]. Many genetic and epigenetic changes have been associated with the development and progression of HCC, such as activation of oncogenes CHD1L4 and SPOCK15, and inactivation of tumor suppressor genes TAT6 and OSGIN17. RNA sequencing (RNA-Seq) was applied to identify genetic alterations between three pairs of HCC tumor and corresponding nontumor samples[8], and overexpression of PIM kinase family members (including PIM1–PIM3) were observed in HCC tumor tissues, among which PIM2 was the most significantly upregulated one. It has been demonstrated that TNFα and IL-6 played pivotal roles in inflammation induced HCC in genetic modified and dietary obesity mouse models[9]
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