The hedgehog (Hh) signaling pathway regulates the development of many organs in mammals, and activation of this pathway is widely observed in human cancers. Although it is known that Hh signaling activates the expression of genes involved in cell growth, the precise role of the Hh pathway in cancer development is still unclear. Here, we show that constitutively activated mutants of Smoothened (Smo), a transducer of the Hh signaling pathway, inhibit the accumulation of the tumor suppressor protein p53. This inhibition was also observed in the presence of Hh ligand or with the overexpression of the transcription factors Gli1 and Gli2, downstream effectors of Smo, indicating that this inhibition is specific for the Hh pathway. We also report that Smo mutants augment p53 binding to the E3 ubiquitin-protein ligase Mdm2 and promote p53 ubiquitination. Furthermore, Hh signaling induced the phosphorylation of human Mdm2 protein on serines 166 and 186, which are activating phosphorylation sites of Mdm2. Smo mutants enhanced the proliferation of mouse embryonic fibroblasts (MEFs) while inducing a DNA-damage response. Moreover, Smo partially inhibited p53-dependent apoptosis and cell growth inhibition in oncogene-expressing MEFs. We also found that accumulation of p53 is inhibited by Hh signaling in several human cancer cell lines. Therefore, the Hh pathway may be a powerful accelerator of oncogenesis by activating cell proliferation and inhibiting the p53-mediated anti-cancer barrier induced by oncogenic stress.

The epidermis is the outermost layer of the skin and provides a protective barrier against environmental insults. It is a rapidly-renewing tissue undergoing constant regeneration, maintained by several types of stem cells. The Hedgehog (HH) signaling pathway is one of the fundamental signaling pathways that contributes to epidermal development, homeostasis, and repair, as well as to hair follicle development and follicle bulge stem cell maintenance. The HH pathway interacts with other signal transduction pathways, including those activated by Wnt, bone morphogenetic protein, platelet-derived growth factor, Notch, and ectodysplasin. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important for elucidating fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in the development and homeostasis epidermis and hair follicles, and in basal cell carcinoma formation, providing an update of current knowledge in this field.

Enhanced glycolysis is important for oncogenesis and for the survival and proliferation of cancer cells in the tumor microenvironment. Recent studies have also shown that proinflammatory cytokine signaling, such as that mediated by nuclear factor κB and signal transducer and activator of transcription 3 (STAT3), is important for the generation of inflammation-associated tumors. However, the link between inflammation and enhanced glycolysis has not been identified. In the present study, we found that the proinflammatory cytokine interleukin (IL)-6 enhanced glycolysis in mouse embryonic fibroblasts and human cell lines. Moreover, STAT3 activated by IL-6 enhanced the expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). Ectopic expression of PFKFB3 enhanced glycolysis, suggesting that the IL-6-STAT3 pathway enhances glycolysis through the induction of these enzymes. Our findings may provide a novel mechanism for inflammation-associated oncogenesis.

Lung cancer is the most common cause of cancer-related death worldwide and is classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Several gene mutations that contribute to aberrant cell proliferation have been identified in lung adenocarcinoma, a part of NSCLC. Various anticancer drugs that target these mutated molecules have been developed for NSCLC treatment. However, although molecularly targeted drugs are initially effective for patients, the 5-year survival rate remains low because of tumor relapse. Therefore, more effective drugs for lung cancer treatment should be developed. The hedgehog (HH) signaling pathway contributes to organ development and stem cell maintenance, and aberrant activation of this signaling pathway is observed in various cancers including lung cancer. In lung cancer, HH signaling pathway upregulates cancer cell proliferation and maintains cancer stem cells as well as cancer-associated fibroblasts (CAFs). Furthermore, physical contact between CAFs and NSCLC cells induces HH signaling pathway activation in NSCLC cells to enhance their metastatic potential. Therefore, HH signaling pathway inhibitors could be a useful option for lung cancer therapy.

The Wnt signaling pathway is essential for embryonic development and carcinogenesis. Upon Wnt stimulation, β-catenin is stabilized and associates with T-cell factor or lymphoid enhancing factor, thereby activating transcription of target genes. In the absence of Wnt stimulation, the level of β-catenin is reduced via glycogen synthase kinase (GSK)-3β-mediated phosphorylation and subsequent proteasome-dependent degradation. Here, we report the identification of Ajuba as a negative regulator of the Wnt signaling pathway. Ajuba is a member of LIM domain-containing proteins that contribute to cell fate determination and regulate cell proliferation and differentiation. We found that enforced expression of Ajuba destabilized β-catenin and suppressed target gene expression. Ajuba promoted GSK-3β-mediated phosphorylation of β-catenin by reinforcing the association between β-catenin and GSK-3β. Furthermore, Wnt stimulation induced both accumulation of β-catenin and destabilization of Ajuba. Our findings suggest that Ajuba is important for regulation of the Wnt signaling pathway.