Effects of miR-193a and sorafenib on hepatocellular carcinoma cells
Alessandro Salvi, Isabel Conde, Edoardo Abeni
1Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa n, 11, 25123 Brescia, Italy. depetro@med.unibs.it.
Background:
Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance, it is the third most common cause of cancer-related mortality worldwide. In the last years the multikinase inhibitor sorafenib has been used for advanced HCC, but some patients do not benefit from this therapy; thus, novel therapeutic options based on molecular approaches are urgently needed. microRNAs are short non coding RNAs involved in several physiological and pathological conditions including HCC and increasing evidence describes miRs as good tools for the molecular targeted therapies in HCC. The purpose of this study was to identify novel approaches to sensitize the HCC cells to sorafenib by microRNAs targeting urokinase-type plasminogen activator (uPA).
Methods:
The miR-193a was validated as negative regulator of urokinase-type plasminogen activator (uPA) in 2 HCC undifferentiated cell lines by transient transfection of miR and anti-miR molecules. The molecular interaction between miR-193a and uPA mRNA target was verified by luciferase reporter assay. The miR-193a expression level was evaluated by stem-loop real time PCR in tumoral tissues from 39 HCC patients. The HCC cells were co-treated with sorafenib and miR-193a and the effects on cellular proliferation, apoptosis were tested. The effect of sorafenib on c-met expression levels was assessed by western blotting.
Results:
The miR-193a has resulted a negative regulator of uPA in both the HCC cell lines tested. The miR-193a expression has resulted dysregulated in tumoral tissues from 39 HCC patients. We found miR-193a down-regulation in HCC respect to peritumoral (PT) tissues and more in the cirrhotic HCCs than in non-cirrhotic ones. Transfection of HA22T/VGH HCC cells with miR-193a decreased proliferation and increased apoptosis, and combined treatment with miR-193a and sorafenib led to further proliferation inhibition.
Conclusions:
Our results present new advances in the post-transcriptional miR-mediated mechanisms of uPA and they suggest a new strategy to impair the aggressive behavior of HCC cells. Our findings could be helpful to explore novel approaches for multi-target and multi-agent therapies of the HCC.
Insights
MicroRNA-193a regulates urokinase-type plasminogen activator (uPA) and sensitizes hepatocellular carcinoma (HCC) cells to sorafenib. This microRNA (miR) could offer novel therapeutic strategies for HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally.
- Sorafenib is a multikinase inhibitor used for advanced HCC, but its efficacy is limited in some patients.
- MicroRNAs (miRs) are emerging as potential molecular targets for novel HCC therapies.
Purpose of the Study:
- To investigate microRNA-193a (miR-193a) as a regulator of urokinase-type plasminogen activator (uPA) in HCC.
- To explore the potential of miR-193a in sensitizing HCC cells to sorafenib treatment.
Main Methods:
- Validated miR-193a as a negative regulator of uPA in HCC cell lines using transfection and luciferase assays.
- Quantified miR-193a expression in HCC patient tissues via stem-loop real-time PCR.
- Assessed the effects of co-treating HCC cells with sorafenib and miR-193a on proliferation and apoptosis.
Main Results:
- miR-193a was confirmed as a negative regulator of uPA in HCC cells.
- miR-193a expression was found to be dysregulated in HCC tissues, with lower levels in tumors compared to peritumoral tissues.
- miR-193a transfection reduced HCC cell proliferation and increased apoptosis; combined treatment with sorafenib enhanced these effects.
Conclusions:
- These findings elucidate novel post-transcriptional miR-mediated mechanisms regulating uPA in HCC.
- miR-193a presents a promising strategy to inhibit aggressive HCC cell behavior.
- The study suggests potential for multi-target, multi-agent therapeutic approaches in HCC treatment.
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