Hypoxia is a common feature of many solid tumors, including hepatocellular carcinoma (HCC). Hypoxia can promote tumor progression and induce radiation and chemotherapy resistance. As one of the major mediators of hypoxic response, hypoxia inducible factor-1 (HIF-1) has been shown to activate hypoxia-responsive genes, which are involved in multiple aspects of tumorigenesis and cancer progression, including proliferation, metabolism, angiogenesis, invasion, metastasis and therapy resistance. It has been demonstrated that a high level of HIF-1 in the HCC microenvironment leads to enhanced proliferation and survival of HCC cells. Accordingly, overexpression, of HIF-1 is associated with poor prognosis in HCC. In this review, we described the mechanism by which HIF-1 is regulated and how HIF-1 mediates the biological effects of hypoxia in tissues. We also summarized the latest findings concerning the role of HIF-1 in the development of HCC, which could shed light on new therapeutic approaches for the treatment of HCC.

BackgroundExosomes are carriers of intercellular information and regulate the tumor microenvironment. They play an important role in drug resistance by transporting RNA molecules and proteins. However, their effects on sorafenib resistance in hepatocellular carcinoma (HCC) are not completely understood.MethodsExosomes were isolated from two invasive hepatoma cell lines (MHCC-97 L and MHCC-97H), and their roles in regulating sorafenib resistance in liver cancer cells as well as the underlying molecular mechanisms were determined. The exosomes were analyzed by TEM (transmission electron microscopy), DLS (dynamic light scattering) and Western blotting. Cell viability, cell death and the effects of exosomes on the HGF/c-Met/Akt signaling pathway in cancer cells were analyzed by MTT assays, FACS analysis and Western blotting, respectively. Moreover, the effects of exosomes on sorafenib resistance in vivo were investigated using a subcutaneous transplantation tumor model in athymic nude mice.ResultsExosomes derived from HCC cells were of the expected size and expressed the exosomal markers CD9 and CD63. They induced sorafenib resistance in vitro by activating the HGF/c-Met/Akt signaling pathway and inhibiting sorafenib-induced apoptosis. They also induced sorafenib resistance in vivo by inhibiting sorafenib-induced apoptosis. Moreover, exosomes derived from highly invasive tumor cells had greater efficacy than that of exosomes derived from less invasive cells.ConclusionsThese data reveal the important role of HCC cell-derived exosomes in the drug resistance of liver cancer cells and demonstrate the intrinsic interaction between exosomes and their targeted tumor cells. This study suggests a new strategy for improving the effectiveness of sorafenib in treating HCC.

Mechanical properties of hydrogels are critical for their applications as articular cartilage regeneration scaffolds, because they provide not only the mechanical support, but also the mechanical cues essential to maintain the phenotype of cartilage‐forming cells. Inspired by the microscopic architecture of natural cartilage, here the engineering of a novel double‐network hydrogel with interconnected polymer‐supramolecular polymer double‐network (PS‐DN gel) for cartilage regeneration is reported. The polymer network is made of polyacrylamide and the supramolecular polymer network comprises of a kind of self‐assembled peptide fibers. Upon mechanical loading, the peptide fibers serve as sacrificial bonds to efficiently dissipate energy. They can quickly reform when mechanical load is released thanks to the fast and accurate peptide self‐assembly. These entail the PS‐DN gel of high mechanical strength of ≈0.32–0.57 MPa, fracture energy of ≈300–2670 J m−2, compressibility of ≈66%–90%, and fast recovery in seconds. The gel also shows significant energy dissipation, strain stiffening, and stress relaxation behaviors similar to articular cartilage. Moreover, the mechanical properties of the PS‐DN gel can be tailored by adjusting the chemical components of the gel. Therefore, this novel biomaterial represents a promising candidate for the regeneration of cartilage and other load bearing tissues.