miR-199a-3p Modulates MTOR and PAK4 Pathways and Inhibits Tumor Growth in a Hepatocellular Carcinoma Transgenic Mouse Model
Elisa CallegariLucilla D’AbundoPaola GuerrieroCarolina SimioniBahaeldin K. ElaminMarta RussoAlice CaniCristian BassiBarbara ZagattiLuciano GiacomelliStella BlandamuraFarzaneh MoshiriSimona UltimoAntonio FrassoldatiGiuseppe AltavillaLaura GramantieriLuca M. NeriSilvia SabbioniMassimo Negrini
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Abstract:
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Prognosis is poor, and therapeutic options are limited. MicroRNAs (miRNAs) have emerged as potential therapeutic molecules against cancer. Here, we investigated the therapeutic efficacy of miR-199a-3p, an miRNA highly expressed in normal liver and downregulated in virtually all HCCs. The therapeutic value of miR-199a-3p mimic molecules was assayed in the TG221 mouse, a transgenic model highly predisposed to the development of liver cancer. Administration of miR-199a-3p mimics in the TG221 transgenic mouse showing liver cancer led to a significant reduction of number and size of tumor nodules compared to control animals. In vivo delivery confirmed protein downregulation of the miR-199a-3p direct targets, mechanistic target of rapamycin (MTOR) and p21 activated kinase 4 (PAK4), ultimately leading to the repression of FOXM1. Remarkably, the anti-tumor activity of miR-199a-3p mimics was comparable to that obtained with sorafenib. These results suggested that miR-199a-3p may be considered a promising HCC therapeutic option.Keywords:
HCCS
Liver Cancer
MiR-122
Liver tumor
Sorafenib is currently used to treat hepatocellular carcinoma (HCC). However, the development of chemoresistance to sorafenib is a major limitation for sorafenib-based therapy in patients with HCC. In the present study, the effect of the combination therapy of sorafenib and wh-4 on the proliferation of liver cancer cells was investigated. The results showed that sorafenib with wh-4 additively suppressed the proliferation of liver cancer cells. The colony formation of liver cancer cells decreased significantly in response to the combination treatment of sorafenib with wh-4, and it also induced the apoptosis of liver cancer cells. Western blot analysis demonstrated decreased expression of Bcl2, and increased expression of Bax in liver cancer cells treated with a combination of sorafenib and wh-4. Moreover, the migration of liver cancer cells was inhibited. The combination treatment of sorafenib with wh-4 reduced the expression levels of ABCB1 and ABCG2 which are responsible for resistance. Finally, STAT3 overexpression abolished the proliferation inhibition effect of sorafenib with wh-4 on liver cancer cells, and sorafenib and wh-4 suppressed the proliferation of liver cancer cells by STAT3 pathway. Together, these results suggest that sorafenib-wh4 combination treatment is a potential novel therapeutic approach to suppress the proliferation of liver cancer cells.
Liver Cancer
Combination therapy
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Liver cancer is one of the most common malignant tumors with a high incidence and mortality. Hepatitis-liver cirrhosis-liver cancer is known as the trilogy of liver cancer. At present, due to significant development of imaging interventions, they occupy an irreplaceable position in the field of liver cancer treatment, especially ultrasound-guided ablation. Because patients with liver cancer often present with liver cirrhosis, which leads to morphological deformation of the liver, it is difficult to perform a linear ablation of liver cancer in the areas near the phrenic top and within large blood vessels, among others. The present study reports on two cases of liver cancer that have been subjected to curvilinear ablation. After 1 mo, magnetic resonance imaging showed complete ablation, demonstrating that ultrasound-guided curved ablation is feasible and effective in the treatment of liver cancer.Two patients were treated at the Liver Disease Department of the Xixi Hospital Affiliated to Zhejiang University of Chinese Medicine in 2019. Because the first liver cancer patient's tumor was located close to the diaphragm, it was difficult to complete a straight needle ablation procedure in one session. In order to achieve accurate and minimally invasive treatment of this tumor, a curved needle ablation procedure was designed. The second patient presented with a hepatic cyst in front of the tumor. In order not to damage the hepatic cyst, a looper needle ablation technique was used. The procedure was successfully completed in both cases.Curved ablation is a new technique that can be used to treat tumors situated in a variety of locations, providing new ideas for interventional techniques. Its operation difficulty is higher and further animal experiments are necessary to improve the operation procedure.
Liver Cancer
Liver tumor
Diaphragm (acoustics)
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Liver Cancer
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Sorafenib is the only molecular targeted drug therapy for advanced liver cancer recommended by the European Association for the study of liver diseases (EASL), American Association for the study of liver diseases (AASLD) and the United States Food and Drug Administration (FDA). As a multi kinase inhibitors, sorafenib can inhibit multiple signal transduction pathways of tumor cell proliferation and angiogenesis and obviously prolong the late stage of disease progression time and overall survival in patients with hepatocellular carcinoma (HCC). Criteria for evaluation of the efficacy of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) is increasingly perfect. The author gives a brief overview of the molecular mechanism, efficacy and safety and efficacy evaluation criteria of sorafenib in the treatment of advanced liver cancer.
Key words:
Sorafenib; Liver cancer; Molecular mechanism; Therapeutic evaluation
Liver Cancer
Liver disease
Targeted Therapy
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MicroRNAs (miRNAs) have been implicated in the orchestration of diverse cellular processes including differentiation, proliferation, and apoptosis and are believed to play pivotal roles as oncogenes and tumor suppressors. miR-122, a liver specific miRNA, is significantly down-regulated in most hepatocellular carcinomas (HCCs) but its role in tumorigenesis remains poorly understood. Here we identify AKT3 as a novel and direct target of miR-122. Restoration of miR-122 expression in HCC cell lines decreases AKT3 levels, inhibits cell migration and proliferation, and induces apoptosis. These anti-tumor phenotypes can be rescued by reconstitution of AKT3 expression indicating the essential role of AKT3 in miR-122 mediated HCC transformation. In vivo, restoration of miR-122 completely inhibited xenograft growth of HCC tumor in mice. Our data strongly suggest that miR-122 is a tumor suppressor that targets AKT3 to regulate tumorigenesis in HCCs and a potential therapeutic candidate for liver cancer.
HCCS
AKT3
MiR-122
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Orthotropic material
Hematology
Liver Cancer
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Sorafenib is a multi-targeted small molecule kinase inhibitors for advanced liver cancer. Clinical trails of sorafenib treatment for phase Ⅲ primary liver cancer showed that it can improve the survival rate of the patients significantly. Interventional treatment,such as radiofrequency ablation and transarterial chemoembolization,has achieved satisfactory clinical results as an important means to treat unresectable advanced hepatocellular carcinoma,which has achieved,which has provided more options for non-operative treatment for advanced liver cancer. The positive effect of sorafenib combined with interventional therapy on advanced liver cancer has been reported in the literatures. Here is to make a review of the biological therapy,interventional therapy for advanced liver cancer,in order to help for clinicians in selecting proper treatment for advanced liver cancer.
Liver Cancer
Targeted Therapy
Hepatocellular cancer
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Sorafenib is currently the first-line treatment for patients with advanced liver cancer, but its therapeutic efficacy declines significantly after a few months of treatment. Therefore, it is of great importance to investigate the regulatory mechanisms of sorafenib sensitivity in liver cancer cells. In this study, we provided initial evidence demonstrating that circPHKB, a novel circRNA markedly overexpressed in sorafenib-treated liver cancer cells, attenuated the sensitivity of liver cancer cells to sorafenib. Mechanically, circPHKB sequestered miR-1234-3p, resulting in the up-regulation of cytochrome P450 family 2 subfamily W member 1 (CYP2W1), thereby reducing the killing effect of sorafenib on liver cancer cells. Moreover, knockdown of circPHKB sensitized liver cancer cells to sorafenib in vivo. The findings reveal a novel circPHKB/miR-1234-3p/CYP2W1 pathway that decreases the sensitivity of liver cancer cells to sorafenib, suggesting that circPHKB and the axis may serve as promising targets to improve the therapeutic efficacy of sorafenib against liver cancer.
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Sorafenib is a new multi-target oral drug that inhibits many kinds of protein kinase small molecules to treat tumors. Currently, sorafenib is one of the drugs that permit systemic treatment of liver cancer in the middle stage. Although sorafenib has good therapeutic effect on liver cancer, the clinical effect of sorafenib alone in the treatment of liver cancer is limited. This study compared the efficacy of sorafenib, TACE (transcatheter arterial chemoembolization), and sorafenib combined with TACE in the treatment of liver cancer patients. The results showed that the curative effect of sorafenib combined with transcatheter arterial chemoembolization is better than that of hepatic artery chemoembolization or sorafenib orally. The total effective rate of combined treatment is 93.8%, while the effective rate of arterial chemoembolization and sorafenib is 64.1% and 72.2% respectively. Combined treatment can significantly prolong the total survival of the patients with liver cancer, which is significantly different from that of arterial chemoembolization or sorafenib alone.
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Liver Cancer
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The self-renewal capacity ascribed to hESCs is paralleled in cancer cell proliferation, suggesting that a common network of genes may facilitate the promotion of these traits. However, the molecular mechanisms that are involved in regulating the silencing of these genes as stem cells differentiate into quiescent cellular lineages remain poorly understood. Here, we show that a differentiated cell specific miR-122 exemplifies this regulatory attribute by suppressing the translation of a gene, Pkm2, which is commonly enriched in hESCs and liver cancer cells (HCCs), and facilitates self-renewal and proliferation. Through a series of gene expression analysis, we show that miR-122 expression is highly elevated in quiescent human primary hepatocytes (hPHs) but lost or attenuated in hESCs and HCCs, while an opposing expression pattern is observed for Pkm2. Depleting hESCs and HCCs of Pkm2, or overexpressing miR-122, leads to a common deficiency in self-renewal and proliferation. Likewise, during the differentiation process of hESCs into hepatocytes, a reciprocal expression pattern is observed between miR-122 and Pkm2. An examination of the genomic region upstream of miR-122 uncovered hyper-methylation in hESCs and HCCs, while the same region is de-methylated and occupied by a transcription initiating protein, RNA polymerase II (RNAPII), in hPHs. These findings indicate that one possible mechanism by which hESC self-renewal is modulated in quiescent hepatic derivatives of hESCs is through the regulatory activity of a differentiated cell-specific miR-122, and that a failure to properly turn "on" this miRNA is observed in uncontrollably proliferating HCCs.
HCCS
MiR-122
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