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A disintegrin and metalloproteinase 10 (ADAM10) has been demonstrated to correlate with hepatocellular carcinoma (HCC) grade and clinical outcome and its potential as a target for HCC therapy has been established. Gene associated with retinoid-interferon-induced mortality 19 (GRIM-19), a signal transducer and activator of transcription 3 (Stat3)-inhibitory protein, was identified as a potential tumor suppressor associated with growth inhibition and cell apoptosis. In the present study, we investigated whether a combined treatment with ADAM10-specific siRNA and GRIM19 gene could have an enhanced anticancer effectiveness on HCC in vitro and in vivo. We developed a dual expression plasmid that co-expressed ADAM10-specific siRNA and GRIM19, to evaluate its effects on HCC growth. Our results showed that simultaneous expression of ADAM10-specific siRNA and GRIM19 (pSi-ADAM10-GRIM19) in HepG2 cancer cells significantly inhibited the proliferation, migration and invasion, and induced cell apoptosis in vitro, and it also suppressed tumor growth in a nude mouse model when compared to the controls, either ADAM10-specific siRNA or GRIM-19 alone. In summary, our data demonstrated that a combined strategy of co-expressed ADAM10-specific siRNA and GRIM19 synergistically and more effectively suppressed HCC tumor growth, and has therapeutic potential for the treatment of HCC.

The objective of the present study was to examine and determine whether the human acute monocytic leukemia cell line THP-1 contains side population (SP) cells, and, if so, to increase the proportion of SP cells using arabinosylcytosine (Ara-C). Fluorescent microscopy and flow cytometry were employed to detect the percentage of SP cells in THP-1 cells. Then, SP and non-SP (NSP) cell subpopulations were collected and identified. THP-1 cells were incubated with different concentrations of Ara-C for 24 h and the proportion of SP cells was detected. Our results demonstrated that the percentage of SP cells was 1.81 ± 0.99% in THP-1 cells. A majority of the SP cells remained in the G₀/G₁ phase, and the expression of CD34⁺ and CD34⁺CD38⁻ and the proliferation ability of the SP cells were higher compared to NSP cells (P

Expression of miR-365 has been reported to be downregulated in hepatocellular carcinoma (HCC). However, the biological function and underlying mechanism of miR-365 in HCC growth and metastasis remain unclear. The aim of the present study was to explore the role of miR-365 in HCC progression. We found that miR-365 expression was downregulated in HCC tissues and cell lines. Further results showed that low expression of miR-365 was significantly associated with tumor-node-metastasis (TNM) stage and lymph node metastasis. Functional assays revealed that overexpression of miR-365 significantly inhibited cell proliferation, colony formation, migration and invasion of HCC cells in vitro, and suppressed tumor growth in vivo. Mechanistic investigations demonstrated that ADAM10 (a disintegrin and metalloproteinase 10) is a target of miR-365 in HCC. In addition, knockdown of ADAM10 in HepG2 cells significantly inhibited cell proliferation, colony formation, migration and invasion, which mimicked the suppressive effects induced by miR-365 overexpression. Restoration of ADAM10 expression partially reversed the suppressive effects mediated by miR-365 overexpression. Taken together, these results indicate that miR-365 functions as a tumor-suppressor in HCC through targeting ADAM10, and may serve as a promising candidate for therapeutic applications in HCC treatment.

Sorafenib (SOR), a vascular endothelial growth factor receptor (VEGFR) inhibitor, is in wide clinical use for the treatment and prevention of liver cancer. However, extended SOR administration for hepatocellular carcinoma (HCC) induces drug resistance thereby limiting its efficacy and highlighting the need for improved therapeutic strategies. It has previously been demonstrated that knockout of a disintegrin and metalloproteinase 10 (ADAM10) via siRNA induced cancer apoptosis and decreased chemotherapy drug resistance. However, whether knockout of ADAM10 is able to decrease SOR resistance remains to be determined. Therefore, in the present study, the effect of siRNA-ADAM10 in combination with SOR was analyzed in HCC cell lines (HepG2) by inhibiting tumor growth and simultaneously reducing doses of SOR. Cell proliferation, apoptosis, migration, invasion and involvement in receptor signaling were determined after siRNA-ADAM10 was applied in combination with SOR treatment. Tumor growth ability in nude mice was also detected. The results showed that siRNA-ADAM10 in combination with SOR treatment in HCC cancer cells significantly suppressed proliferation, migration and invasion, and induced tumor apoptosis in vitro, and suppressed tumor growth in vivo. In addition, the results showed that knockout of ADAM10 by siRNA inhibited the constitutive phosphorylation of PI3K and AKT, which may contribute to the reduction of SOR resistance. Collectively, our experimental results indicate that knockout of ADAM10 by siRNA increased the SOR antitumor activity of liver cancer in vitro and in vivo, and that this additive combination is a promising drug candidate for treatment of HCC.