Abstract
Therapies for primary liver cancer, the third leading cause of cancer-related death worldwide, remain limited. Following multi-omics analysis (including whole genome and transcriptome sequencing), we were able to identify the dual-specific protein kinase TTK as a putative new prognostic biomarker for liver cancer. Herein, we show that levels of TTK protein are significantly elevated in neoplastic tissues from a cohort of liver cancer patients, when compared with adjacent hepatic tissues. We also tested the utility of TTK targeted inhibition and have demonstrated therapeutic potential in an experimental model of liver cancer in vivo. Following lentiviral shRNA knockdown in several human liver cancer cell lines, we demonstrated that TTK boosts cell growth and promotes cell spreading; as well as protects against senescence and decreases autophagy. In an experimental animal model, we show that in vitro knockdown of TTK effectively blocks intrahepatic growth of human HCC xenografts. Furthermore, we note that, in vivo silencing of TTK, by systemically delivering TTK siRNAs to already tumor-bearing liver, limits intrahepatic spread of liver cancer cells. This intervention is associated with decreased tumor aggressiveness, as well as increased senescence and autophagy. Taken together, our data suggest that targeted TTK inhibition might have clinical utility as an adjunct therapy in management of liver cancer.
Highlights
A better biomarker would allow for better clinical stratification and may facilitate highly individualized and targeted treatment of liver cancer
Western blot results showed that TTK protein levels recapitulated mRNA expression patterns in 34 pairs of hepatitis B virus (HBV)-Hepatocellular carcinoma (HCC) tumor and adjacent noncancerous liver tissues[8]: protein levels of TTK were significantly increased in liver cancer tissues, when compared to noncancerous liver tissues (P = 9.8 × 10−12) (Fig. 1A,B and Fig. S1)
In order to circumvent TTK antibody-created non-specificity in both Western blot and immunohistochemical staining[10], we preformed a preliminary RNAscope in situ hybridization (ISH) assay using freshly made formalin-fixed, paraffin-embedded tissue blocks from a HBV-HCC patient
Summary
A better biomarker would allow for better clinical stratification and may facilitate highly individualized and targeted treatment of liver cancer. We found that heightened intratumoral expression of TTK correlates with aggressive clinical course and low survival in liver cancer[8]. Liang et al demonstrated that TTK is associated with acquired sorafenib-resistance in various liver cancer cell lines[9]. Little is still known regarding the role of TTK in hepatocarcinogenesis. We have put forward the hypothesis that TTK has pro-carcinogenic roles in HCC development and progression. Directed TTK blockade might serve as an effective therapeutic target. We have evaluated the role of TTK in in vitro cell culture systems and developed studies of therapeutic utility in pre-clinical in vivo animal models
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