Abstract
Liver cancer is the fourth leading cause of cancer-related mortality worldwide with limited therapeutic options. Thus, novel treatment strategies are urgently required. While the oncogenic kinase, proviral integration site for Moloney murine leukemia virus 2 (PIM2), has been shown to be overexpressed in liver cancer, little is known about the role of PIM2 in this tumor entity. In this study, we explored the functional relevance and therapeutic potential of PIM2 in liver cancer. Using PIM2-specific siRNAs, we examined the effects of PIM2 knockdown on proliferation (WST-1 assays and spheroid assays), 3D-colony formation and colony spread, apoptosis (flow cytometry and caspase 3/caspase 7 activity), as well as cell cycle progression (flow cytometry, RT-qPCR and western blot analysis) in the two liver cancer cell lines, HepG2 and Huh-7. In subcutaneous liver cancer xenografts, we assessed the effects of PIM2 knockdown on tumor growth via the systemic delivery of polyethylenimine (PEI)-complexed siRNA. The knockdown of PIM2 resulted in potent anti-proliferative effects in cells grown on plastic dishes, as well as in spheroids. This was due to G0/G1 cell cycle blockade and the subsequent downregulation of genes related to the S phase as well as the G2/M phase of the cell cycle, whereas the apoptotic rates remained unaltered. Furthermore, colony formation and colony spread were markedly inhibited by PIM2 knockdown. Notably, we found that HepG2 cells were more sensitive to PIM2 knockdown than the Huh-7 cells. In vivo, the therapeutic nanoparticle-mediated delivery of PIM2 siRNA led to profound anti-tumor effects in a liver cancer xenograft mouse model. On the whole, the findings of this study underscore the oncogenic role of PIM2 and emphasize the potential of targeted therapies based on the specific inhibition of PIM2 in liver cancer.
Highlights
Liver cancer is one of the most frequent malignant tumors with a high prevalence in Eastern and South‐Eastern Asia, and rising incidence rates in the Western world
Three PIM2‐specific siRNAs were tested in the liver cancer cell lines, HepG2 and Huh‐7
PIM2 is overexpressed as well, but little is known about the functional relevance of PIM2 in this tumor entity
Summary
Liver cancer is one of the most frequent malignant tumors with a high prevalence in Eastern and South‐Eastern Asia, and rising incidence rates in the Western world. It is the fourth leading cause of cancer‐related mortality worldwide, due to high rates of late‐stage diagnosis and limited treatment options [1,2]. Proviral integration site for Moloney murine leukemia virus 2 (PIM2) belongs to a family of constitutively active serine/threonine kinases comprising 3 members, PIM1, PIM2 and PIM3 These proto‐oncogenes are involved in several cellular processes, including cell survival/apoptosis, cell cycle progression, migration and invasion [3,4,5]. PIM1 has been explored most extensively so far, with PIM1 inhibitors being tested in clinical studies as a monotherapy or in combined treatment strategies, predominantly in patients with hematological cancers [11]
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