CT45A1Acts As A New Proto-oncogene To Trigger Tumorigenesis And Cancer Metastasis

In recent years, malignant tumor is more and more serious harm to the health andlife of the people in our country. Although, tumor diagnosis and therapy have madesome progress, there is only a little improvement in overall. One of the main reasons isthat the pathogenesis of the malignant tumor is still enigmatic, and specific markers ofearly clinical diagnosis and effective anti-tumor therapeutic target still lack.Malignant tumor have "atavism", and abnormally overexpression of someembryonic period gened related to fast growth and development, including someoncogenes and Cancer/Testis antigens(CTAs), and these embryonic gene has been silentin normal adult. Carcinogenesis is a dynamic process dependent on not only theoncogenic properties of cancer cells, but also dependent on a favored environment inorgans. In particular, genetic and epigenetic abnormalities arise in a hostile tumormicroenvironment, leading to activation of various proto-oncogenes, to producenumerous oncogenes, resulting in tumor initiation, progression, and metastasis.Based on the above analysis, we used bioinformatics analysis to systematic searchfor and analysis of the expression profile of cancer stem cell and malignant tumor cell.After a large number of high throughput screening, we got a number of candidate genes,including some CTAs. Accumulated data show that, CTAs are not expressed in nearlyall tissues after birth, except for the testis, but are highly expressed in cancers, and areclosely associated with poor overall survival of cancer patients. Presently, more than200CT genes have been identified. However, whether CTAs exert an oncogene-likefunction is still unknown.CT45gene family (CT45) belongs to CTAs. CT45is comprised of six genesdesignated as CT45A1to CT45A6. The amino acid sequences exhibit more than98%identity among the six CT45family members. CT45exists only in Homo sapiens and10other primates, and not in any other species. In the normal human, CT45is onlyexpressed in testis, and not in any other tissues, but overexpressed in various malignanttumors, including lung cancer, breast cancer, and so on. Notably, overexpression of CT45is closely associated with tumor progression, aggressiveness, and poor prognosis.Despite the close association of CT45overexpression with poor prognosis of cancerpatients, the biological function of CT45is still less studied. Whether CT45A1acts as anew proto-oncogene to trigger tumorigenesis is still unclear.In the current study, we used low tumorigenic breast cancer MCF7cells, whichlack CT45A1and other CT45family members, as a model to explore the oncogeniceffect of the gene and its mechanisms. Using breast cancer as a model, we found thatCT45A1, a representative CT45family member, alone had a weak tumorigenic effect.However, its neoplastic potency was greatly enhanced in the presence of growth factors.Overexpression of CT45A1in breast cancer cells markedly up-regulated variousoncogenic and metastatic genes, constitutively activated ERK and CREB signalingpathways, promoted epithelial-mesenchymal transition, and increased cell stemness,tumorigenesis, invasion, and metastasis; while silencing CT45A1significantly reducedcancer cell migration and invasion. We propose that CT45A1functions as a novelproto-oncogene to trigger oncogenesis and metastasis. CT45A1and other CT45members are valuable genes in the study of a molecular phylogenetic tree, and excellenttargets for anti-cancer drug discovery and targeted tumor therapy.