Abstract
Stemness factors control microRNA expression in cancer stem cells. Downregulation of miR-100 and miR-125b is associated with tumor progression and prognosis of various cancers. Comparing miRNA profiling of patient-derived tumorsphere (TS) and adherent (2D) hepatocellular carcinoma cells, miR-100 and miR-125b are identified to have association with stemness. In TS cells, miR-100 and miR-125b were downregulated comparing to 2D cells. The finding was reproduced in Hep3B cells. Overexpression of stemness factors NANOG, OCT4 and SOX2 by introduction of gene constructs in Hep3B cells suppressed these two miRNA expression levels. Treatment of chromeceptin, an IGF signaling pathway inhibitor, decreased numbers of TS and inhibited the AKT/mTOR pathway. Stable cell line of miR-100 and miR-125b overexpression decreased IGF2 expression and inhibited tumor growth in the xenograft model. In conclusion, miR-100 and miR-125b have tumor suppressor role in hepatocellular carcinoma through inhibiting IGF2 expression and activation of the AKT/mTOR pathway.
Highlights
Stemness factors control microRNA expression in cancer stem cells
The TS cancer cells from four hepatocellular carcinoma (HCC) patients grew with a spherical shape in the low attachment dish with a specific media (Fig. 1A, right, Supplementary Fig. 1A), while spheroids were not formed in a collagen type 1 dish (Fig. 1A, left, Supplementary Fig. 1A)
The expression levels of hsa-miR-125b and hsa-miR-100 at the mature Micro RNAs (miRNAs) were significantly downregulated in TS cells compared to those in 2D cells in the qRT-PCR analysis (Fig. 1B)
Summary
Stemness factors control microRNA expression in cancer stem cells. Downregulation of miR-100 and miR-125b is associated with tumor progression and prognosis of various cancers. Comparing miRNA profiling of patient-derived tumorsphere (TS) and adherent (2D) hepatocellular carcinoma cells, miR-100 and miR-125b are identified to have association with stemness. Overexpression of stemness factors NANOG, OCT4 and SOX2 by introduction of gene constructs in Hep3B cells suppressed these two miRNA expression levels. Stable cell line of miR-100 and miR-125b overexpression decreased IGF2 expression and inhibited tumor growth in the xenograft model. MiR-100 and miR-125b have tumor suppressor role in hepatocellular carcinoma through inhibiting IGF2 expression and activation of the AKT/mTOR pathway. Several miRNAs, such as miR-134, miR-296, and miR-470, behave as mediators of pluripotency, self-renewal, and differentiation of cancer stem cells by controlling the stemness factors NANOG, OCT4, and S OX24–6. CSCs differ in their miRNA expression profile especially in miRNAs that regulate the expression of genes related to self-renewal and differentiation properties of CSCs10. Carcinoma had similar mechanism in the maintenance of stemness by upregulation of complement proteins C7 and CFH, and through NANOG, OCT4, SOX2, and c-Myc expression[15]
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