MicroRNAs (miRNAs) have been shown to be dysregulated in virus-related cancers; however, miRNA regulation of virus-related cancer development and progression remains poorly understood. Here, we report that miR-148a is repressed by hepatitis B virus (HBV) X protein (HBx) to promote cancer growth and metastasis in a mouse model of hepatocellular carcinoma (HCC). Hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP) is an important regulator of cancer cell growth. We used miRNA target prediction programs to identify miR-148a as a regulator of HPIP. Expression of miR-148a in hepatoma cells reduced HPIP expression, leading to repression of AKT and ERK and subsequent inhibition of mTOR through the AKT/ERK/FOXO4/ATF5 pathway. HBx has been shown to play a critical role in the molecular pathogenesis of HBV-related HCC. We found that HBx suppressed p53-mediated activation of miR-148a. Moreover, expression of miR-148a was downregulated in patients with HBV-related liver cancer and negatively correlated with HPIP, which was upregulated in patients with liver cancer. In cultured cells and a mouse xenograft model, miR-148a reduced the growth, epithelial-to-mesenchymal transition, invasion, and metastasis of HBx-expressing hepatocarcinoma cells through inhibition of HPIP-mediated mTOR signaling. Thus, miR-148a activation or HPIP inhibition may be a useful strategy for cancer treatment.

We previously identified a pivotal role for G protein α inhibitory subunit 1 (Gαi1) in mediating PI3K-Akt signaling by receptor tyrosine kinases (RTKs). Here, we examined the expression and biological function of Gαi1 in human glioma. Gαi1 mRNA and protein expression were significantly upregulated in human glioma tissues, which correlated with downregulation of an anti-Gαi1 miRNA: microRNA-200a ("miR-200a"). Forced-expression of miR-200a in established (A172/U251MG lines) and primary (patient-derived) human glioma cells resulted in Gαi1 downregulation, Akt inactivation and proliferation inhibition. Reduction of Gαi1 expression by shRNA, dominant negative mutant interference, or complete Gαi1 depletion inhibited Akt activation and cell proliferation. Notably, miR-200a was unable to inhibit glioma cell proliferation when Gαi1 was silenced or mutated. Co-immunoprecipitation studies, in human glioma cells and tissues, show that Gαi1 forms a complex with multiple RTKs (EGFR, PDGFRα, and FGFR) and the adapter protein Gab1. In vivo, the growth of subcutaneous and orthotopic glioma xenografts in nude mice was largely inhibited by expression of Gαi1 shRNA or miRNA-200a. Collectively, miR-200a downregulation in human glioma leads to Gαi1 over-expression, Akt activation and glioma cell proliferation.

It is well known that stem cells reside within tissue engineering functional microenvironments that physically localize them and direct their stem cell fate. Recent efforts in the development of more complex and engineered scaffold technologies, together with new understanding of stem cell behavior in vitro, have provided a new impetus to study regulation and directing stem cell fate. A variety of tissue engineering technologies have been developed to regulate the fate of stem cells. Traditional methods to change the fate of stem cells are adding growth factors or some signaling pathways. In recent years, many studies have revealed that the geometrical microenvironment played an essential role in regulating the fate of stem cells, and the physical factors of scaffolds including mechanical properties, pore sizes, porosity, surface stiffness, three-dimensional structures, and mechanical stimulation may affect the fate of stem cells. Chemical factors such as cell-adhesive ligands and exogenous growth factors would also regulate the fate of stem cells. Understanding how these physical and chemical cues affect the fate of stem cells is essential for building more complex and controlled scaffolds for directing stem cell fate.

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