Limited sorafenib anticancer effects on primary cultured hepatocellular carcinoma cells with high NANOG expression

Abstract

Cancer stem cell is considered as an important cause to exacerbate the prognosis. NANOG and POU5F1 are markers for cancer stem cells. The associations between NANOG and POU5F1 expressions with the sorafenib anticancer effects in primary cultured hepatocellular carcinoma (HCC) cells were investigated. Eight primary cultured HCC parent cell lines and 13 subgroups established by flow cytometric sorting using NANOG and POU5F1 as targets were investigated with clinically achievable sorafenib plasma concentrations (5 and 10 μg/mL). Sorafenib showed obvious downregulation of RAF/MEK/ERK signaling pathways and dose-dependent anti-proliferative effects only on s003 parent cell line, which showed the lowest expression of NANOG among all tested cell lines except one downregulated NANOG with upregulated POU5F1 s020 subgroup. Sorafenib also inhibited proliferation in this s020 subgroup but promoted proliferation in its parent cell line. For the only one downregulated NANOG alone s015 subgroup, sorafenib which had no influence on its parent cell line inhibited proliferation in this subgroup. Only the above three cell lines could demonstrate sorafenib antiproliferative effects. On the contrary, sorafenib promoted proliferation in three (s003, s015, s071) out of four upregulated NANOG alone subgroups. On the other hand, Sorafenib showed diverse influence on proliferation among four upregulated POU5F1 alone subgroups. In conclusion, NANOG rather than POU5F1 expression is a critical marker for the anticancer effects of sorafenib on HCC. The sorafenib anticancer effects on HCC cells with high NANOG expression were limited. Sorafenib should be combined with other drug able to target cancer cells with high NANOG expression.