Hypoxia is a common feature of stable tumors and an important contributor to anti-tumor drug resistance. cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally HIF-1α overexpression rescued and HIF-1α knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore miR-338-3p sensitized HCC cells to sorafenib and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1α. Collectively miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1α. Our data show that miR-338-3p could be a potential candidate for HCC therapeutics. Intro Hepatocarcinoma (HCC) is one of the most common human being malignancies causing more than 600 0 deaths worldwide each year. Although half of instances and deaths were estimated to occur in China the incidence is increasing not only in Rabbit Polyclonal to PKC zeta (phospho-Thr410). Asia but also in the USA Europe and Africa [1]. Treatment options for HCC include medical resection liver transplantation radioimmunotherapy and chemotherapy. The choice of treatment depends OSI-930 on the malignancy stage source availability and practitioner choices [2]. Chemotherapy is an important therapeutic strategy for individuals who are in advanced phases of disease but are not candidates for surgery [3]. Sorafenib a multi-kinase OSI-930 inhibitor is the only clinically authorized drug for individuals with advanced OSI-930 HCC [4]; however high rates of sorafenib resistance in HCC individuals often prevent its long-term effectiveness [5]. Consequently novel focuses on and methods are needed to successfully treat this fatal tumor. Hypoxia is commonly observed in malignant neoplastic cells as tumors increase in size but lack neurovascularization [6]. Hypoxia-inducible element (HIF)-1 is definitely a transcription element that mediates cell adaptive reactions to hypoxia by regulating a series of genes implicated in angiogenesis glucose uptake rate of metabolism and cell proliferation [7]. As a consequence of intratumoral hypoxia HIF-1 was found to be overexpressed and play important tasks in the pathogenesis and pathophysiology of HCC [8]-[10]. Recent studies suggested that tumor hypoxia results in chemotherapy resistance and that HIF-1 plays a critical part in hypoxia-induced chemoresistance. [10]-[12]. Like a encouraging therapeutic target for HCC HIF-1 when inhibited offers OSI-930 been shown to suppress tumor growth and to reverse chemoresistance [13]-[15]. HIF-1 is definitely a heterodimer protein composed of an oxygen-sensitive HIF-1α subunit and a constitutively indicated HIF-1β subunit [16]. Although oxygen-dependent post-translational changes is the main mechanism of HIF-1α build up HIF-1α can also be transcriptionally and translationally controlled by signaling molecules such as growth factors cytokines and microRNAs [17]. MicroRNA is definitely a class of small endogenous non-coding RNA molecules that control gene manifestation by focusing on mRNAs for cleavage or repression of translation. [18] miRNAs are differentially indicated in normal cells and cancers and contribute to malignancy development and progression [19]. With this study we found that miR-338-3p directly targeted HIF-1α and suppressed the HIF signaling pathway. We examined the tumor suppressor properties of miR-338-3p in HCC cells and in nude mice. Furthermore our data showed that miR-338-3p potentiated growth inhibitory function of sorafenib in HCC. Materials and Methods Samples Study involving human being participants was authorized by the institutional review table at Harbin Medical University or college. Written consent was given by all the individuals according to the Declaration of Helsinki and recorded. None of them of the individuals in the study received chemotherapy or radiation therapy before surgery. Cell lines The human being hepatoma cell lines HepG2 SMMC-7721 BEK-7402 Hep3B and Huh-7 and the liver cell collection L02 were purchased from your cell standard bank of type tradition collection in the Chinese Academy of Sciences (Shanghai China). Sorafenib (sc-220125A) was purchased from Santa Cruz Biotechnology (Santa Cruz CA) and dissolved in DMSO. The final DMSO concentration was lower than 0.1%. Hypoxia treatment Hypoxia treatment was carried out as previously explained [20]. Briefly cells were placed in a sealed hypoxia chamber equilibrated with qualified gas comprising 1% O2 5 CO2 and 94% N2. RNA extraction and real time PCR (RT-PCR) Total miRNA was extracted using the TRIzol reagent.