West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, Renmin Nanlu, Chengdu 610041, People's Republic of China.
Metallomics. 2020 Jun 24;12(6):963-973. doi: 10.1039/d0mt00076k.
Linc-ROR is an oncogenic long non-coding RNA over-expressed in many kinds of cancer that promotes cancer cell proliferation. Arsenite is a determined carcinogen that increases the risk of skin cancer, but the carcinogenic mechanism of arsenite remains unclear. To explore whether and how linc-ROR plays a role in arsenite-induced carcinogenesis of skin cancer, we established arsenite-transformed keratinocyte HaCaT cells by exposing them to 1 μM arsenite for 50 passages. Then we examined the linc-ROR expression during the transformation and explored the effect of linc-ROR on the cell proliferation of arsenite-transformed HaCaT cells. We found that the linc-ROR level in HaCaT cells was gradually increased during arsenite-induced malignant transformation, and the activity of P53 was decreased, but the P53 expression was not significantly altered, indicating that linc-ROR may play a role in arsenite-induced HaCaT cell transformation that is associated with P53 activity but not P53 expression. We further demonstrated that linc-ROR down-regulation by siRNA significantly inhibited the cellular proliferation and restored P53 activity in arsenite-transformed HaCaT cells, suggesting that linc-ROR promotes proliferation of arsenite-transformed HaCaT cells by inhibiting P53 activity. Moreover, linc-ROR siRNA also down-regulated the PI3K/AKT pathway in arsenite-transformed HaCaT cells, and treatment with AKT inhibitor wortmannin restored P53 activity, implying that linc-ROR inhibits P53 activity by activating the PI3K/AKT pathway. Taken together, the present study shows that linc-ROR promotes arsenite-transformed keratinocyte proliferation by inhibiting P53 activity through activating PI3K/AKT, providing a novel carcinogenic mechanism of arsenite-induced skin cancer.
Linc-ROR 是一种在多种癌症中过度表达的致癌性长非编码 RNA，可促进癌细胞增殖。砷是一种确定的致癌物质，会增加皮肤癌的风险，但砷的致癌机制尚不清楚。为了探讨 linc-ROR 是否以及如何在砷诱导的皮肤癌细胞癌变中发挥作用，我们通过将 HaCaT 细胞暴露于 1μM 砷 50 代来建立砷转化的角质形成细胞。然后，我们在转化过程中检查了 linc-ROR 的表达，并探讨了 linc-ROR 对砷转化的 HaCaT 细胞增殖的影响。我们发现，在砷诱导的恶性转化过程中，HaCaT 细胞中的 linc-ROR 水平逐渐升高，P53 的活性降低，但 P53 的表达没有明显改变，这表明 linc-ROR 可能在与 P53 活性而非 P53 表达相关的砷诱导 HaCaT 细胞转化中发挥作用。我们进一步证明，siRNA 下调 linc-ROR 可显著抑制砷转化的 HaCaT 细胞的细胞增殖并恢复 P53 的活性，表明 linc-ROR 通过抑制 P53 的活性促进砷转化的 HaCaT 细胞的增殖。此外，linc-ROR siRNA 还下调了砷转化的 HaCaT 细胞中的 PI3K/AKT 通路，而 AKT 抑制剂wortmannin 恢复了 P53 的活性，这表明 linc-ROR 通过激活 PI3K/AKT 抑制 P53 的活性。总之，本研究表明，linc-ROR 通过激活 PI3K/AKT 抑制 P53 的活性，从而促进砷转化的角质形成细胞增殖，为砷诱导的皮肤癌的致癌机制提供了新的见解。
