Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, it is the third most common cause of cancer-related mortality worldwide. Surgical resection and liver transplantation are first-line curative options for patients with early stage HCC, as they confer 5-year survival rates of 70%. Locoregional therapies such as transarterial chemoembolization and radiofrequency ablation are care for patients not suitable for surgery [
1‐
3]. In recent years the multikinase inhibitor sorafenib has been used to treat advanced HCCs improving the overall survival of HCC patients from 7.9 months to 10.7 months and it is the sole systemic drug that is proved to be effective in this disease [
4,
5]. For this reason, efforts that focus on the implementation of personalized medicine approaches in HCC in the next years will be a challenge. It is well known that microRNAs (miRs) control a wide range of physiological and pathological processes, including cancer [
6]. Dysregulation of miRs may play a relevant role in hepatocarcinogenesis and HCC progression [
7]. For example, the hepatospecific miR-122 is significantly downregulated in more than 50-70% of HCCs and this loss of miR-122 expression is correlated with poor prognosis and metastasis of liver cancer [
8]. In contrast, miR-21, miR-221 and miR-224 are generally reported to be upregulated in HCC tissues [
9‐
11]. Several studies indicate that miRNAs expression may have clinical relevance as biomarkers for HCC stratification, early diagnosis or the follow-up of patients [
12]. Additionally, studies showing that miRNAs themselves or anti-miRNA oligonucleotides can be successfully used for
in vitro and
in vivo modulation of miRNA actions have indicated significant potentials for molecular targeted therapy [
13,
14]. Additional studies have shown that some miRs may sensitize or improve the effects of the more conventional therapies in HCC cells. For example, an miR-122 mimetic alone or in combination with sorafenib reduced the tumourigenic properties of HCC cells and may therefore be a promising therapeutic regimen for liver cancer [
15]. Chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic. In HCC patients treated with cisplatin-based chemotherapy, miR-199a-5p levels were significantly reduced; forced expression of miR-199a-5p promoted the cisplatin-induced inhibition of cell proliferation [
16]. The resistance of HCC cells to 5-FU is mediated by miR-193a-3p
via inhibition of the expression of serine/arginine-rich splicing factor 2 (SRSF2) expression. In turn, SRSF2 preferentially up-regulates the proapoptotic splicing form of caspase 2 (CASP2L) and sensitizes HCC cells to 5-FU. Forced changes of miR-193a-3p level were shown to reverse the 5-FU sensitivity, in cell culture and in
nude mice [
17]. It is well known that the serine protease urokinase type plasminogen activator (uPA) is a responsive therapeutic target for HCC and others malignancies and its overexpression correlates with tumour invasion and metastasis [
18‐
22]. In this work, to study the co-treatment of HCC cells with sorafenib and miRNAs targeting uPA we have first validated the miR-193a-3p as a negative regulator of uPA in HCC cells; furthermore, we have tested the effects of miR-193a-3p in combination with sorafenib.