CAMPTOTHECIN INHIBITS MIGRATION, INVASION AND CLONOGENIC PROPERTY OF LIVER CANCER CELLS BY MODULATING MICRORNA EXPRESSION
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Camptothecin (CPT), an alkaloid natural product, extracted from Camptotheca acuminata bark, has been reported to have potential antitumor activity in diverse cancers. MicroRNAs (MiRNAs) are a class of short, non-coding RNAs that plays a crucial role in the normal physiology by attenuating translation. Here, we showed that the CPT modulates the expression of miRNAs in hepatocellular carcinoma cells (HCC). Microarray analysis reveals that CPT modulates the expression of as many as 39 miRNAs in HCC cells (Huh7), 27 miRNAs were downregulated whereas 12 miRNAs were upregulated. miR-16 is the key miRNA upregulated by CPT and targets key prosurvival proteins (MMP-2, MMP-9 and cyclin D1). Our results demonstrate that CPT is inhibiting cell viability of HCC cells significantly when compared with the untreated cells. Wound healing and colony formation assay confirm inhibition of cell migration and clonogenic property of Huh7 cells respectively, upon the dose-dependent treatment of CPT. Furthermore, the Boyden chamber assay analysis revealed a significant inhibition of number of invasive cells in CPT treated cells with comparison to untreated Huh7 cells. Mechanistically, CPT upregulates miR-16 expression which targets MMP-2, MMP-9, cyclin D1 downregulation and subsequently upregulates the expression of E-cadherin, TIMP1, p21, and p27, thereby inhibits cell migration, invasion and clonogenic property of HCC cells. In summary, CPT treatment in Huh7 cells decreases cell viability and upregulates miR-16 expression, which results in inhibition of cell migration, invasion and clonogenic property of cells, by decreasing MMP-2, MMP-9, cyclin D1 and increasing the expression of cell cycle-regulated proteins p21 and p27.
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