SUMMARY Many signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to up-regulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming.

ADAM9 (A disintegrin and a metalloprotease 9) is a membrane-anchored protein that participates in a variety of physiological functions, primarily through the disintegrin domain for adhesion and the metalloprotease domain for ectodomain shedding of a wide variety of cell surface proteins. ADAM9 influences the developmental process, inflammation, and degenerative diseases. Recently, increasing evidence has shown that ADAM9 plays an important role in tumor biology. Overexpression of ADAM9 has been found in several cancer types and is correlated with tumor aggressiveness and poor prognosis. In addition, through either proteolytic or non-proteolytic pathways, ADAM9 promotes tumor progression, therapeutic resistance, and metastasis of cancers. Therefore, comprehensively understanding the mechanism of ADAM9 is crucial for the development of therapeutic anti-cancer strategies. In this review, we summarize the current understanding of ADAM9 in biological function, pathophysiological diseases, and various cancers. Recent advances in therapeutic strategies using ADAM9-related pathways are presented as well.

Lung cancer is a leading cause of cancer death due to the high incidence of metastasis; therefore novel and effective treatments are urgently needed. A current strategy is cancer specific targeted gene therapy. While many identified cancer specific promoters are highly specific, they tend to have low activity compared to the ubiquitous CMV promoter, limiting their application. We developed a targeted gene therapy expression system for lung cancer that is highly specific with strong activity. Our expression vector uses the survivin promoter, highly expressed in many cancers but not normal adult tissues. We enhanced the survivin promoter activity comparable to the CMV promoter in lung cancer cell lines using an established platform technology, while the survivin promoter remained weak in normal cells. In mouse models, the transgene was specifically expressed in the lung tumor tissue, compared with the CMV promoter that was expressed in both normal and tumor tissues. Additionally, the therapeutic gene BikDD, a mutant form of pro-apoptotic Bik, induced cell killing in vitro, and inhibited cell growth and prolonged mouse survival in vivo. Importantly, there was virtually no toxicity when BikDD was expressed with our expression system. Thus, the current report provides a therapeutic efficacy and safe strategy worthy of development in clinical trials treating lung cancer.