Abstract
MicroRNA 155 (miRNA-155) is frequently dysregulated in hepatocellular carcinoma (HCC) and other cancer types. Toll-like receptor 3 (TLR3), a putative miR-155 target, plays a key role in liver pathophysiology, and its downregulation in HCC cells is associated with apoptosis evasion and poor outcomes. Herein, we examined the ability of in situ self-assembled Au-antimiR-155 nanocomplexes (Au-antimiRNA NCs) to activate TLR3 signaling in HCC cells. Gene expression analysis confirmed an inverse relationship between miR-155 and TLR3 expression in HCC samples, and marked upregulation of miR-155 was observed in HCC cells but not in normal L02 hepatocytes. RNA immunoprecipitation confirmed physical interaction between miR-155 and TLR3, while negative regulation of TLR3 expression by miR-155 was demonstrated by luciferase reporter assays. Au-antimiR-155 NCs were self-assembled within HepG2 HCC cells, but not within control L02 cells. They efficiently silenced miR-155, thereby inhibiting proliferation and migration and inducing apoptosis in HepG2 cells. Molecular analyses suggested these effects are secondary to TLR3 signaling mediating NF-κB transcription, caspase-8 activation, and interleukin-1β (IL-1β) release. Our results provide a basis for future studies examining the in vivo applicability of this novel Au-antimiRNA NCs delivery system to halt HCC progression by activating pro-apoptotic TLR3 signaling.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancerrelated deaths in the world [1]
These findings suggest that the anti-proliferative and proapoptotic effects of Au-antimiR-155 NCs in HCC cells are mediated by activation of Toll-like receptor 3 (TLR3) signaling, leading to upregulation of NF-κB expression, activation of caspase-8, and induction of IL-1β
Several studies advanced the potential of TLR3 as a therapeutic target for hepatoma, melanoma, and clear cell renal carcinoma [20, 33,34,35], the mechanisms mediating its antitumor effects remain insufficiently characterized [36]
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancerrelated deaths in the world [1]. The distribution of population risk factors for HCC is highly variable and may change according to the geographic region examined and to racial or ethnic group composition [2]. Xinjiang is a multi-ethnic settlement region in northwestern China. Xinjiang’s ethnic Kazakhs have traditional distinctive living habits and dietary structures. Research suggested that distinct pathogenic features characterize HCC development or progression in Kazakh people and other minorities in the Xinjiang region [3]. The incidence of HCC in Xinjiang’s Kazakhs ranks sixth among all tumors and third among malignancies of the digestive tract. Despite being considered a population at high-risk for HCC [4], the pathogenic mechanisms of HCC within this demographic group have not yet been elucidated
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