The Functions And Mechanisms Of TCF-4 In Cutaneous Squamous Cell Carcinoma

Skin cancers are arisen from the uncontrolled growth of abnormal skin cells which primarily developed on the exposure to ultraviolet(UV)radiation from sunlight or tanning beds.Skin cancers are classified basal cell carcinoma,cutaneous squamous cell carcinoma(cSCC)and melanoma.Epidemiologic studies have declared that cSCC accounts for 20% of total skin cancer with the continuously increasing incidence worldwide and poses a threat for public health.Currently,research demonstrates that cSCC is diagnosed at a rate of 15–35 per 100,000 people and is expected to increase 2–4 % per year.A significant subset of cSCC has the propensity for poor outcomes.Besides the cause of UV exposure,the genetic reasons especially the disabled DNA damage repair for UV induced cyclobutene pyrimidine dimers contribute to the cSCC development.Moreover,the regulatory network for cell growth,apoptosis and invasion had also attracted the attention in carcinogenesis of cSCC.Due to the metastasis ability of cSCC which make cSCC more dangerous than other kinds of skin cancer,so it is very important for better understanding cSCC to strengthen study on prevention and cure.T-cell factor 4(TCF-4)is a member of T cell factor/ lymphoid enhancer factor(TCF/LEF)family.TCF-4 protein contains four key functional domains including β-catenin binding domain,HMG-box domain,Groucho binding domain,and nuclear localization signal domain.TCF-4 has been determined to activate Wnt/β-catenin signaling pathway in multiple cancers including CRC,PDAC and PCa,etc.Silencing the aberrant expression of TCF-4 can efficiently repress the tumor cell growth and proliferation,which indicates that TCF-4 plays an oncogenic role and can be served as a potential therapeutic target for cancer treatment.As mentioned earlier,TCF-4 plays a key role in epidermal stem cells,but the roles and the underlying mechanism of TCF-4 in the carcinogenesis and development of cSCC are not fully understood.In this study,we found that TCF-4 was highly expressed in cSCC of carcinoma tissue rise.Then we established the A431 cell line with TCF-4 silencing to confirm that the proliferation and invasion of the A431 cells with TCF-4 silencing were repressed,and the apoptosis was enhanced by MTT,Transwell and TUNEL experiments.Furthermore RNA-Seq was conducted and observed that 147 genes were up-regulated(including 113 coding genes and 34 lncRNA)while 172 genes were down-regulated(including 64 coding genes and 108 lncRNA)in TCF-4 silencing compared to blank RNAi and untreated control A431 cells.Besides,18 pathways including steroid,porphyrin,arachidonic acid and retinol metabolism as well as the functions associated with angiogenesis,inflammatory response and cell adhesion were involved in the differentially expressed genes of A431 cells with TCF-4 silencing.Finally,the TCF-4 and β-catenin were performed and we found that the enrichments of β-catenin were lost on the promoters on top ten down-regulated genes in A431 cells with TCF-4 silencing compared to the untreated A431 by ChIP-qPCR experiment.Additionally,some genes such as ALDH8A1,DRICH1 and UGT1A5 were observed with high enrichment of TCF-4 but without β-catenin in untreated A431 cells,which indicated a Wnt/β-catenin independent way of TCF-4 for gene transcriptional regulation.In conclusion,we declared that TCF-4 played an important role in tumorigenesis of skin cancer via the aberrant activation of variety of signaling pathways,and could be considered as a potential therapeutic target for cSCC treatment.