CK2α causes stemness and chemotherapy resistance in liver cancer through the Hedgehog signaling pathway.

BACKGROUND: Liver cancer is one of the major causes of cancer-related deaths globally. Cancer cell stemness and chemotherapy resistance contribute to the high mortality. Although evidence indicates that the alpha subunit of protein kinase 2 (CK2α) is involved in several human cancers, its function in liver cancer remains unknown. In the present study, we aimed to elucidate the role of CK2α in liver cancer. METHODS: We examined the role of CK2α regulation in stemness and chemotherapy resistance capacity of liver cancer cells. MTT assays, tumor sphere formation assays, RT-PCR, flow cytometry, Western blotting assay, clonogenicity assay, matrigel invasion assay and bioinformatics were conducted in this study. RESULTS: CK2α expression in the liver cancer tissues was notably upregulated compared with that in the corresponding non-tumorous tissues. The overexpression of CK2α promoted tumor sphere formation, increased the percentage of CD133(+) and side population cells, caused the resistance of liver cancer cells to 5-FU treatment, increased the expression levels of NANOG, OCT4, SOX2, Gli1 and Ptch1, and enhanced the ability of CD133(+) cell clone formation and invasion. Consistently, the downregulation of CK2α had the opposite effects. CK2α silencing inhibited the Hedgehog pathway by reducing the expression of Gli1 and Ptch1. Mechanistically, CK2α regulation on liver cancer cell stemness and chemotherapy resistance was found to be involved in the Hedgehog signaling pathway. CONCLUSIONS: Our study may bring some new insights into the occurrence of liver cancer. Furthermore, these findings suggest that targeting CK2α may be a novel therapeutic strategy for patients with liver cancer.

Epithelial-mesenchymal transition during oncogenic transformation induced by hexavalent chromium involves reactive oxygen species-dependent mechanism in lung epithelial cells.

Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Exposure to Cr(VI) induces DNA damage, cell morphological change and malignant transformation in human lung epithelial cells. Despite extensive studies, the molecular mechanisms remain elusive, it is also not known if Cr(VI)-induced transformation might accompany with invasive properties to facilitate metastasis. We aimed to study Cr(VI)-induced epithelial-mesenchymal transition (EMT) and invasion during oncogenic transformation in lung epithelial cells. The results showed that Cr(VI) at low doses represses E-cadherin mRNA and protein expression, enhances mesenchymal marker vimentin expression and transforms the epithelial cell into fibroblastoid morphology. Cr(VI) also increases cell invasion and promotes colony formation. Further studies indicated that Cr(VI) uses multiple mechanisms to repress E-cadherin expression, including activation of E-cadherin repressors such as Slug, ZEB1, KLF8 and enhancement the binding of HDAC1 in E-cadherin gene promoter, but DNA methylation is not responsible for the loss of E-cadherin. Catalase reduces Cr(VI)-induced E-cadherin and vimentin protein expression, attenuates cell invasion in matrigel and colony formation on soft agar. These results demonstrate that exposure to a common human carcinogen, Cr(VI), induces EMT and invasion during oncogenic transformation in lung epithelial cells and implicate in cancer metastasis and prevention.

Anti-apoptotic proteins and catalase-dependent apoptosis resistance in nickel chloride-transformed human lung epithelial cells.

Chronic exposure to nickel compounds is associated with increased incidence of certain types of human cancer, including lung and nasal cancers. Despite intensive investigation, the oncogenic processes remain poorly understood. Apoptosis resistance is a key feature for tumor cells to escape physiological surveillance and acquire growth advantage over normal cells. Although NiCl2 exposure induces transformation of human lung epithelial cells, little information is available with regard to its molecular mechanisms, it is also not clear if the transformed cells are apoptosis resistant and tumorigenic. We explored the apoptosis resistance properties of nickel chloride­transformed human lung epithelial cells and the underlying mechanisms. The results showed that transformed BEAS-2B human lung epithelial cells are resistant to NiCl2-induced apoptosis. They have increased Bcl-2, Bcl-xL and catalase protein levels over the passage matched non­transformed counterparts. The mechanisms of apoptosis resistance are mitochondria­mediated and caspase-dependent. Forced overexpression of Bcl-2, Bcl-xL and catalase proteins reduced NiCl2-induced cell death; siRNA­mediated knockdown of their expression sensitized the cells to nickel-induced apoptosis, suggesting that Bcl-2, Bcl-xl and catalase protein expression plays a critical role in apoptosis resistance. Akt also participates in this process, as its overexpression increases Bcl-xL protein expression levels and attenuates NiCl2-induced apoptosis. Furthermore, transformed cells are tumorigenic in a xenograft model. Together, these results demonstrate that nickel-transformed cells are apoptosis­resistant and tumorigenic. Increased expression of Bcl-2, Bcl-xL and catalase proteins are important mechanisms contributing to transformed cell oncogenic properties.