Activation of sonic hedgehog (Shh) signaling has been implicated in progression of a variety of tumors. In this study, we elucidated a role for Shh in the invasion of gastric tumors and determined the mechanism by which Shh is regulated. Immunohistochemical analysis of 178 primary human gastric tumor biopsies indicated that Shh expression was positively correlated with lymph node metastasis, high lymphatic vessel density, and poor prognosis. In mouse xenograft models of human gastric cancer, enforced expression of Shh significantly enhanced the incidence of lung metastasis compared with nonexpressing controls. Mechanistic investigations revealed that phosphoinositide 3-kinase (PI3K)/Akt inhibition blocked Shh-induced epithelial-mesenchyme transition, the activity of matrix metalloproteinase 9 (MMP-9), and lymphangiogenesis, reducing tumor invasiveness and metastasis. Taken together, our findings establish that Shh signaling promotes the metastasis of gastric cancer through activation of the PI3K/Akt pathway, which leads to mesenchymal transition and MMP-9 activation. These findings offer preclinical validation of Shh as a candidate therapeutic target for treatment of metastatic gastric cancers. Cancer Res; 71(22); 7061-70. Ó2011 AACR.

The tumor suppressor p53 binds prosurvival Bcl-2 family proteins such as Bcl-w and Bcl-X L to liberate Bax, which in turn exerts proapoptotic or anti-invasive functions depending on stress context. On the basis of our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here, we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-X L also served as a target of the cooperative action of p53 and p21. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Cancer Res; 77(11); 3092-100. Ó2017 AACR.

The p53 protein arrests the cell cycle at the G 1 phase when stabilized by the interaction between ribosomal proteins and HDM2 under growth-inhibitory conditions. Meanwhile, p53, when translocated to the mitochondria in response to cell death signals, induces apoptosis via transcription-independent mechanisms. In this report, we demonstrate that the mitochondrial ribosomal protein L41 (MRPL41) enhances p53 stability and contributes to p53-induced apoptosis in response to growth-inhibitory conditions such as actinomycin D treatment and serum starvation. An analysis of MRPL41 expression in paired normal and tumor tissues revealed lower expression in tumor tissue. Ectopic MRPL41 expression resulted in inhibition of the growth of cancer cells in tissue culture and tumor growth in nude mice. We discovered that MRPL41 protein is localized in the mitochondria, stabilizes the p53 protein, and enhances its translocation to the mitochondria, thereby inducing apoptosis. Interestingly, in the absence of p53, MRPL41 stabilizes the p27 Kip1 protein and arrests the cell cycle at the G 1 phase. These results suggest that MRPL41 plays an important role in p53-induced mitochondrion-dependent apoptosis and MRPL41 exerts a tumor-suppressive effect in association with p53 and p27Kip1 .

Intravenous administration of mesenchymal stem cells (MSCs) has served as a clinical intervention for inflammatory diseases. Once entered to blood circulation, MSCs are exposed to a harsh environment which sharply decreases cell viability due to the fact that injected cells, being susceptible to shear stress, are subjected to the high velocities of the bloodstream and lack of proper mechanical support that keeping them in an attachment-deprived state. Here, we coated the nanofilm onto viable MSCs by depositing poly-l-lysine and hyaluronic acid molecules along with arginine-glycine-aspartic acid (RGD peptide) as building blocks to protect cells from shear stress and stabilize them in a single cell, suspension state. In this article, we found that nanofilm-coated cells showed significantly increased cell survival in vitro and in vivo, which was also supported by the activation of survival-related protein, Akt. The coated nanofilm did not interfere with the stemness of MSCs which was determined based on the colony forming unit-fibroblast (CFU-F) assay and in vitro differentiation potential. Because of the characteristics of films showing light molecular deposition density, flexibility, and looseness, application of nanofilms did not block cell migration. When the cells were administrated intravenously, the nanofilm coated MSCs not only prolonged blood circulation lifetime but also showed increased stem cell recruitment to injured tissues in the muscle injury in vivo model, due to prolonged survival. Surface modification of MSCs using nanofilms successfully modulated cell activity enabling them to survive the anoikis-inducing state, and this can provide a valuable tool to potentiate the efficacy of MSCs for in vivo cell therapy.