Suppressing Dicer inhibits proliferation and contributes to cellular senescence, partially via a p21-associated senescence pathway.

Abstract

Dicer is known to engage in regulating micro (mi)RNA biosynthesis. However, the role in driving thyroid carcinogenesis is unknown. In this study, we explored the role of Dicer in the carcinogenesis of well-differentiated thyroid carcinoma (WDTC). Thyroid cancer complementary (c)DNA and tissue arrays were purchased to measure Dicer messenger (m)RNA and protein levels. Additionally, research into silencing Dicer1 in papillary thyroid cancer (PTC) (TPC-1), follicular thyroid cancer (FTC), and normal thyroid (Nthy-ori 3-1) cell lines was also applied to evaluate its effects on tumour behaviors. Dicer1 mRNA was upregulated in PTC, while the Dicer protein was overexpressed in PTC and FTC tissues. Suppressing Dicer led to inhibition of cell proliferation in all cell lines, and repression of cell-cycle progression signatures in TPC-1 cells. Furthermore, p21 expression consistently increased in response to compromising Dicer in all four cell lines. Finally, Dicer1-knockdown TPC-1 and Nthy-ori 3-1 cells demonstrated nuclear phospho-H2AX staining, reduced bromodeoxyuridine incorporation ability, and G1 phase arrest of the cell cycle. Collectively, Dicer expression is increased in WDTC clinical samples, and Dicer regulates the proliferative ability of normal and WDTC cells, at least in part, through p21-dependent modulation of a cell-senescence mechanism linked to genomic instability.