Axin acts as a negative regulator in Wnt signaling through interaction with various molecules involved in this pathway, including beta-catenin, adenomatous polyposis coli, and glycogen synthase kinase 3beta. We show here that Axin also regulates the effects of Smad3 on the transforming growth factor beta (TGF-beta) signaling pathway. In the absence of activated TGF-beta receptors. Axin physically interacted with Smad3 through its C-terminal region located between the beta-catenin binding site and Dishevelled-homologous domain. An Axin homologue, Axil (also called conductin), also interacted with Smad3. In the absence of ligand stimulation, Axin was colocalized with Smad3 in the cytoplasm in vivo. Upon receptor activation, Smad3 was strongly phosphorylated by TGF-beta type I receptor (TbetaR-I) in the presence of Axin, and dissociated from TbetaR-I and Axin. Moreover, the transcriptional activity of TGF-beta was enhanced by Axin and repressed by an Axin mutant which is able to bind to Smad3. Axin may thus function as an adapter of Smad3, facilitating its activation by TGF-beta receptors for efficient TGF-beta signaling.

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.

CD24 is a heavily glycosylated cell surface protein that is expressed in putative stem cells and is overexpressed in various human malignancies, yet the significant roles of CD24 in gastric cancer development are still elusive. We investigated the involvement of CD24 in gastric cancer aggressiveness, which is attributed to its heterogeneity. Cultured gastric cancer cells showed diverse expression patterns in CD24, whereas other defined cell surface markers, such as CD44 and CD133, were homogenous. Purely sorted CD24‐negative gastric cancer cells showed strong alteration into the CD24‐positive cell type in an autochthonous manner, and reached to steady expression levels. Our clinicopathological study revealed that CD24 positivity was an independent prognostic factor in both intestinal and diffuse types of gastric cancer. CD24 expression was correlated with the advanced stages, invasiveness, and lymph node metastasis of gastric cancer. Silencing of CD24 in cultured cells significantly decreased cell migration and invasion. Hypoxic treatment upregulated CD24 expression, and simultaneously induced cell motility and invasion of gastric cancer cells. Hypoxic treatment‐induced CD24 expression was significantly attenuated by knockdown of hypoxia‐inducible transcription factors. These data suggest that CD24‐negative cells are capable of gaining cell motility and invasiveness through the induction of CD24, which is mediated by hypoxia. CD24 would be an attractive marker to define not only the heterogeneity but also the aggressiveness of gastric cancer cells. The mechanisms by which hypoxia induces CD24 expression would also be a potential therapeutic target for gastric cancer.