Abstract
Germinal center kinase-like kinase (GLK) is a key controller of autoimmunity. In this study, we assessed the clinical relevance and tumorigenic effects of GLK in hepatocellular carcinoma (HCC). Using immunohistochemistry, we showed that the GLK proportion score increased in both cancerous and adjacent non-cancerous liver tissue from patients with HCC recurrence. A Kaplan-Meier analysis revealed that patients with a wide distribution of GLK in non-cancerous liver tissue had a higher rate of HCC recurrence than those with very low or no GLK expression. Multivariate Cox regression analyses indicated that a high GLK proportion score in non-cancerous liver tissue was an independent predictor of early HCC recurrence after resection. Lentiviral vector-mediated overexpression of GLK activated the nuclear factor kappa B (NFκB) signaling cascade and accelerated cell cycle progression in primary human hepatocytes, thereby promoting proliferation. An increase in GLK expression coincided with NFκB activation and enhanced expression of proliferating cell nuclear antigen in HCC tissue. Our findings demonstrate a potential hepatocarcinogenic effect of GLK and the feasibility of using GLK to predict early HCC recurrence.
Highlights
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths globally [1]
We investigated the clinical relevance of Germinal center kinase-like kinase (GLK) in early hepatocellular carcinoma (HCC) recurrence, and elucidated the effects of GLK activity on hepatocyte proliferation
We previously demonstrated that GLK induces protein kinase C (PKC)-θ phosphorylation at Thr538 and hyperactivation of NFκB, which is crucial for the progression of T helper (Th) 17 cell-mediated autoimmune disease [12]
Summary
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths globally [1]. There are approximately three quarters of a million new cases of HCC and 700,000 deaths from HCC each year. Advances in imaging techniques for early detection, surgical methods, and the development of novel therapies have drastically improved the prognosis of patients with HCC and www.impactjournals.com/oncotarget minimized complications [4, 5]. The high rate of recurrence following hepatic resection substantially reduces the overall survival of patients. Relapse is the major cause of death of HCC patients but the factors that drive HCC recurrence are incompletely understood. It is imperative to identify a marker for predicting early recurrence and patient prognosis, and for facilitating the optimal clinical management of patients following hepatectomy
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