Effects of miR-193a and sorafenib on hepatocellular carcinoma cells

Abstract

BackgroundHepatocellular 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).MethodsThe 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.ResultsThe 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.ConclusionsOur 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.

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

“…However, treatment outcomes are poor due to unfavorable pharmacokinetics, low tumor accumulation and high rates of sorafenib resistance in HCC patients (5). Evidence has shown that, some miRNAs increased sorafenib sensitivity to HCC cells (13,(38)(39)(40). In addition, inhibition of the activation of Akt may be a valid approach to treating human malignancies and overcoming the resistance of cancer cells to chemotherapy (41).…”

MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1

“…Recent studies have revealed that miR-193a-3p is associated with apoptosis and proliferation in cancer cells (25,26). We examined two markers of apoptosis, PARP and caspase-3, to investigate the alteration in apoptosis after the introduction of miR-193a-3p in DSS-induced colitis.…”

“…Recent studies have revealed that miR-193a-3p is associated with apoptosis and proliferation of human malignancies, such as hepatocellular carcinoma and glioblastoma. Kwon et al (26) presented a novel miR-193a-3p-dependent mechanism for regulating Mcl-1 expression and inducing apoptosis, whereas Salvi et al (25) found that miR-193a-3p was dysregulated in tumor tissues from patients, and transfection of miR-193a-3p decreased proliferation and increased apoptosis in HCC cell lines. We also analyzed PARP cleavage and caspase-3 activation to investigate the alteration in apoptosis after miR-193a-3p was introduced in DSS-induced colitis.…”

miR-193a-3p Functions as a Tumor Suppressor in Lung Cancer by Down-regulating ERBB4

“…Dysregulation of miR193a-3p has been reported in various types of cancer, such as NSCLC (29), prostate cancer (30), breast cancer (31), head and neck squamous cell carcinoma (32), colorectal cancer (33), myeloid leukemia (34), and Wilms tumor (35). The carcinogenic impact of miR-193a-3p has been attributed to its repression of c-Kit (34) and the PTEN/PI3K signaling pathway in acute myeloid leukemia (34); of KRAS and PLAU in colon cancer (36); of PLAU (37) and EGFR-driven cell cycle network proteins (38) in breast cancer; of ARHGAP19, CCND1, ERBB4, KRAS, and Mcl-1 in epithelial ovarian cancer (39); of PLAU in hepatocellular carcinoma (40); and of Mcl-1 in NSCLC (41). Thus, miR-193a-3p functions as a tumor suppressor in human cancers.…”