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MicroRNA-216a: a potential therapeutic target for drug resistance and recurrent of liver cancer
To the Editor:
We read with great interest the article MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer published in Hepatology. Epigenetic changes are found in hepatocellular carcinoma (HCC), in particular, deregulation of microRNA-216a (miR-216a) cluster in HCC tissue samples and cell lines was associated with sorafenib resistance and tumor metastases. miR-216a is significantly overexpressed in the early recurrent HCC cells. miR-216a plays an important role in mediating HCC pathogenesis, drug resistance and recurrence in HCC.[1]
Pathway analysis indicated that PI3K/AKT and TGF-β signalings were affected by overexpression of miR-216a through the effector protein, phosphatase and tensin homolog (PTEN) deleted on chromosome 10. Recent studies[2, 3] demonstrated that PTEN could be repressed by selectively changing miRNAs in HCC. Jung et al[2] found that the PTEN expression was strongly down-regulated in samples from patients with aberrant expression of certain miRNAs. Furthermore, Xia et al[1] indicated that overexpression of miR-216a activates PI3K/AKT and TGF-β pathways through the down-regulation of PTEN, these pathway alternations result in an acquired resistance to sorafenib. The activation of the PI3K/AKT pathway plays a critical role in drug resistance which leads to unfavorable treatment outcome, whereas the blockade of the PI3K/AKT pathway by sorafenib improves the anti-tumor activity of rapamycin in HCC.[4] Similarly, down-regulation of the PI3K/AKT pathway reverses multidrug resistance gained by HCC.[5] Meanwhile, the TGF-β cytokine, a unique cytokine in the molecular pathogenesis of cancer, initiates some signaling cascades (e.g. ERK, AKT, Smad) which were closely linked to drug resistance in HCC.[6-8] It has been found that TGF-β induced AKT activation was mediated by miR-216a-modulated PTEN suppression, suggesting that the inhibition of miR-216a/PTEN/AKT signaling might be a novel strategy for HCC prevention and management.[7] Interestingly, Chen et al[9] revealed that the elevation of miR-216a was mainly identified in male patients, which implies that androgen plays an important role in the up-regulation of miR-216a in hepatocarcinogenesis. It may be worth identifying a possible relationship between miR-216a and gender in HCC.
In conclusion, these findings may give a therapeutic potential target for drug resistance and recurrence of liver cancer. However, further studies are still needed to clarify the mechanisms of miR-216a in HCC. We could believe that therapeutic agents targeting miR-216a might result in innovative therapies for HCC.
Institute for Liver Diseases of Anhui Medical University, School of Pharmacy,
Anhui Key Laboratory of Bioactivity of Natural Products,
Anhui Medical University, Hefei 230032, China
Tel/Fax: 86-551-65161001;
Email: lj@ahmu.edu.cn
References
1 Xia H, Ooi LL, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology 2013;58:629-641. PMID: 23471579
2 Jung CJ, Iyengar S, Blahnik KR, Jiang JX, Tahimic C, Torok NJ, et al. Human ESC self-renewal promoting microRNAs induce epithelial-mesenchymal transition in hepatocytes by controlling the PTEN and TGFβ tumor suppressor signaling pathways. Mol Cancer Res 2012;10:979-991. PMID: 22622027
3 Huang S, He X. The role of microRNAs in liver cancer progression. Br J Cancer 2011;104:235-240. PMID: 21102580
4 Jiao M, Nan KJ. Activation of PI3 kinase/Akt/HIF-1α pathway contributes to hypoxia-induced epithelial-mesenchymal transition and chemoresistance in hepatocellular carcinoma. Int J Oncol 2012;40:461-468. PMID: 21922131
5 Li QL, Gu FM, Wang Z, Jiang JH, Yao LQ, Tan CJ, et al. Activation of PI3K/AKT and MAPK pathway through a PDGFRβ-dependent feedback loop is involved in rapamycin resistance in hepatocellular carcinoma. PLoS One 2012;7:e33379. PMID: 22428038
6 Tanahashi T, Osada S, Yamada A, Kato J, Yawata K, Mori R, et al. Extracellular signal-regulated kinase and Akt activation play a critical role in the process of hepatocyte growth factor-induced epithelial-mesenchymal transition. Int J Oncol 2013;42:556-564. PMID: 23229794
7 Wu K, Ding J, Chen C, Sun W, Ning BF, Wen W, et al. Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology 2012;56:2255-2267. PMID: 22898879
8 Liu ZM, Tseng JT, Hong DY, Huang HS. Suppression of TG-interacting factor sensitizes arsenic trioxide-induced apoptosis in human hepatocellular carcinoma cells. Biochem J 2011;438:349-358. PMID: 21649584
9 Chen PJ, Yeh SH, Liu WH, Lin CC, Huang HC, Chen CL, et al. Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis. Hepatology 2012;56:632-643. PMID: 22392644
(doi: 10.1016/S1499-3872(13)60104-6) |