Cancer/testis antigen (CTA)-45 family (CT45) belongs to a new family of genes in phylogenetics and is absent in normal tissues except for testis, but is aberrantly overexpressed in various cancer types. Whether CT45 and other CTAs act as proto-oncogenes has not been determined. Using breast cancer as a model, we found that CT45A1, a representative CT45 family member, alone had a weak tumorigenic effect. However, its neoplastic potency was greatly enhanced in the presence of growth factors. Overexpression of CT45A1 in breast cancer cells markedly upregulated various oncogenic and metastatic genes, constitutively activated ERK and CREB signaling pathways, promoted epithelial–mesenchymal transition, and increased cell stemness, tumorigenesis, invasion, and metastasis, whereas silencing CT45A1 significantly reduced cancer cell migration and invasion. We propose that CT45A1 functions as a novel proto-oncogene to trigger oncogenesis and metastasis. CT45A1 and other CT45 members are therefore excellent targets for anticancer drug discovery and targeted tumor therapy, and valuable genes in the study of a molecular phylogenetic tree.

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Oncogenic epithelial-mesenchymal transition (oncEMT) plays important roles in the genesis of cancer stem cells (CSCs), malignant tumor initiation and progression, cancer metastasis, and drug resistance. Although the role of oncEMT in tumorigenesis has recently been extensively studied, the initiation of oncEMT is not clearly understood, and its mechanisms of action are still unknown. Emerging evidence suggests that oncEMT is a complex process, which involves multiple endogenous and exogenous factors. Overexpression of several oncogenes and reprogramming factors in precancerous and cancerous cells, including Ras, Myc, Bmi-1, Oct4, Nanog, Slug, Twist, Zeb1, and Zeb2, may initiate oncEMT and tumorigenesis. Defects in key tumor suppressors, such as p53, PTEN, CCN6 protein, and p21 also are associated with oncEMT. MicroRNA (miRNA) may also play a role in the oncEMT. Furthermore, exogenous factors, including chemical carcinogens, viruses, radiation, hypoxia, and acidic microenvironment, can drive oncEMT. Moreover, various growth factors derived from either malignant tumor cells or tumor-associated non-tumor cells in the cancer microenvironment can promote oncEMT. Together, the endogenous and exogenous factors, as well as a hostile cancer microenvironment, initiate the oncEMT program through diverse signaling pathways and networks. However, the dynamic process of initiating oncEMT and the mechanisms are still incompletely understood. Further characterization of the dynamics and mechanisms of the oncEMT will provide new insights into oncogenesis, as well as identify specific oncEMT markers and targets for early diagnosis of cancer and novel anti-cancer drug discovery.

RAD18 is an E3 ubiquitin-protein ligase that has a role in carcinogenesis and tumor progression owing to its involvement in error-prone replication. Despite its significance, the function of RAD18 has not been fully examined in colorectal cancer (CRC). In the present research, by collecting clinical samples and conducting immunohistochemical staining, we found that RAD18 expression was significantly increased in the CRC tissue compared with that noted in the adjacent non-cancerous normal tissues and that high expression of RAD18 was associated with lymph node metastasis and poor prognosis in CRC patients. In vitro, as determined by cell transfection, scratch, and Transwell experiments, it was also demonstrated that RAD18 increased the invasiveness and migration capacity of CRC cells (HCT116, DLD-1, SW480). The signaling pathway was analyzed by western blotting and the clinical data were analyzed by immunohistochemical staining and RT-PCR, indicating that the process of epithelial-mesenchymal transition (EMT) may be involved in RAD18-mediated migration and invasion of CRC cells. All of the above data indicate that RAD18 is a novel prognostic biomarker that may become a potential therapeutic target for CRC in the future.