MicroRNA-221 overexpression accelerates hepatocyte proliferation during liver regeneration

Abstract

The tightly controlled replication of hepatocytes in liver regeneration and uncontrolled proliferation of tumor cells in hepatocellular carcinoma (HCC) are often modulated by common regulatory pathways. Several microRNAs (miRNAs) are involved in HCC progression by modulating posttranscriptional expression of multiple target genes. miR‐221, which is frequently up‐regulated in HCCs, delays fulminant liver failure in mice by inhibiting apoptosis, indicating a pleiotropic role of miR‐221 in hepatocytes. Here, we hypothesize that modulation of miR‐221 targets in primary hepatocytes enhances proliferation, providing novel clues for enhanced liver regeneration. We demonstrate that miR‐221 enhances proliferation of in vitro cultivated primary hepatocytes. Furthermore, applying two‐thirds partial hepatectomy as a surgically induced liver regeneration model we show that adeno‐associated virus‐mediated overexpression of miR‐221 in the mouse liver also accelerates hepatocyte proliferation in vivo. miR‐221 overexpression leads to rapid S‐phase entry of hepatocytes during liver regeneration. In addition to the known targets p27 and p57, we identify Aryl hydrocarbon nuclear translocator (Arnt) messenger RNA (mRNA) as a novel target of miR‐221, which contributes to the pro‐proliferative activity of miR‐221. Conclusion: miR‐221 overexpression accelerates hepatocyte proliferation. Pharmacological intervention targeting miR‐221 may thus be therapeutically beneficial in liver failure by preventing apoptosis and by inducing liver regeneration. (HEPATOLOGY 2013;)

An Artificially Designed Interfering lncRNA Expressed by Oncolytic Adenovirus Competitively Consumes OncomiRs to Exert Antitumor Efficacy in Hepatocellular Carcinoma

“…These miRNAs execute different biologic functions through acting on different target genes and different signal transduction pathways during the occurrence and development of HCC. These miRNAs can be categorized according to their functions as follows: miR21, miR221/222, miR224, miR17-5p/20a, miR10b, miR106b, miR151-5p, miR155, miR181a/181b, and miR184 can promote the proliferation, invasion, and metastasis of HCC cells (12)(13)(14)(15)(16)(17); miR221/222, miR224, miR10b, and miR155 can inhibit HCC cell apoptosis (13,18,19,21); and miR21, miR221/222, miR143, miR1, and miR501-5p can promote the replication of HBV, induce carcinogenesis, and enhance cancer cell proliferation (36)(37)(38).…”

“…The miRNAs that are highly expressed in hepatocellular carcinoma (HCC) include miR21 (11), miR221/222 (11,12), miR224 (13), miR17-5p/20a (14), miR10b (15), miR106b (16), miR151-5p (17), miR155 (18), miR181a/181b (19), miR184 (20), etc. These miRNAs play different roles in the tumorigenesis and progression of HCC (21,22).…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…Indeed, they show how a Staphylococcal nuclease domain-containing 1 (SND1) protein stimulates NF-kB and miR-221 resulting in the overexpression of angiogenic factors such as angiogenin and CXCL16. Additional mechanisms are explained by Yuan et al (2013). miR-221 leads to an increase of cell proliferation through the induction of the S phase of the cell cycle having as molecular targets p27 and p57.…”

Fígado e luz. Uma combinação precisa, da mitologia à medicina

“…A fotobioestimulação baseia-se no nível mais sutil de interação da luz com tecidos, em que o fóton transmite sua energia a um composto fotossensível. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] Pressupõe-se que a luz laser conduza a alterações conformacionais na estrutura dos citocromos dos hepatócitos, de modo que haveria um incremento na produção de ATP, expressando um aumento no metabolismo energético de fí-gado de ratos hepatectomizados. 16,20 Foi demonstrado que a luz laser, tanto de alta quanto baixa potência, tem a capacidade de elevar o índice mitótico e função mitocondrial no remanescente hepático após ressecções parciais em ratos não cirróticos.…”

“…A perda tecidual rapidamente desencadeia o processo regenerativo até que o peso original seja recuperado. A constatação da resposta do fígado aos vários desafios, como as hepatites, as intoxicações, as ressecções hepáticas e o transplante de fíga-do, é mitológica [8][9][10][11][12] e levanta aspectos extremamente interessantes sobre a coerência do fígado em superar desafios e vencer obstáculos. Hesíodo relatou, em sua Teogônia, escrita no século VIII a.C., que Prometeu roubou o fogo escondido no Olimpo para entregá-lo aos homens.…”