RBP2 Induces Epithelial-Mesenchymal Transition In Non-Small Cell Lung Cancer And Esophageal Squamous Cancer

Lung cancer is the most common cause of cancer mortality, and its morbidity is increasing worldwide. In male malignant tumors, both morbidity and mortality of lung cancer top the list. In female malignant tumors, the morbidity of lung cancer is in second place, behind breast cancer. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer. Unfortunately, many NSCLC patients develop distant metastasis during the early stage of the disease. Moreover, mortality among NSCLC patients is more often caused by metastasis rather than their primary tumors. Therefore, the early detection and prevention of metastasis is a key step in stopping the progression of NSCLC.Esophageal cancer is a common malignant tumor in digestive system. In the world, the number of people who die from esophageal cancer is about 300000 per year. Its morbidity and mortality is greatly difference in various countries. Our country is one of the high prevalence areas of esophageal cancer. About 150000 people die from esophageal cancer each year. The morbidity is much higher in men than women. The typical symptom of esophageal cancer is progressive dysphagia, which seriously affects the quality of life.RBP2 is a new histone demethylases for tri-and dimethylated lysine 4 on histone H3 (H3-K4me2 and H3K4me3), which has been found to actively participate in cancer progression. It has an AT-rich interaction domain (ARID) that specifically recognizes the DNA sequence CCGCCC. This special DNA sequence is enriched in the promoter regions of the RBP2 target genes. In gastric cancer, RBP2 binds to the promoter regions of the pl6ink4a, p21CIP1 and p27kipl genes to inhibit their expressions and diminish the senescence of cancer cells. In lung cancer, RBP2 binds to the promoter region of p27, cyclin D1 and integrin β1 to mediate cancer cell proliferation and metastasis.EMT is a pivotal step in cancer metastasis. During this process, cancer cells derived from epithelial cells lose their epithelial characteristics, such as cellular adhesion, but acquire mesenchymal characteristics, such as cell motility, to escape from the primary tissue and invade the surrounding stroma. Epithelial cadherin (E-cadherin), a cell adhesion molecule, is a key molecule of EMT. It plays a vital role in maintaining the epithelial phenotype. The absence of E-cadherin leads to a loss of epithelial morphology. Interestingly, the reduced expression of E-cadherin is often accompanied by increased expression of neural cadherin (N-cadherin). N-cadherin has been shown to weaken cell adhesion and promote breast cancer cell invasiveness. Snail is another important molecule of EMT. It has been confirmed that snail overexpression enhances cancer invasion by promoting cell motility.In this study, we analyzed the effects of RBP2 on epithelial-mesenchymal transition in non-small cell lung cancer. The results showed that:(1) RBP2 was overexpressed in NSCLC; (2) RBP2 could enhance NSCLC cellular migration; (3) the expression of RBP2 was significantly inversely correlated with the expression of E-cadherin; (4) the overexpression of RBP2 induced epithelial-mesenchymal transition in NSCLC; (5) RBP2 down-regulated the expression of E-cadherin by inhibiting the promoter activity of E-cadherin; (6) RBP2 up-regulated the expression of N-cadherin and snail via the activation of Akt signaling.Subsequently, we investigated the effects of RBP2 on EMT in esophageal squamous cancer and further compared the effects of RBP2 on the expression of E-cadherin in lung squamous cancer cells and in esophageal squamous cancer cells. The results showed that RBP2 played a similar role in esophageal squamous cancer, suggesting that the effect of RBP2 on EMT may commonly exist in solid tumors. E-cadherin plays a pivotal role in the tumorigenesis, development and prognosis of cancer. E-cadherin methylation is positively associated with tumor size, histological grade and lymphatic metastasis in breast cancer. Abnormal expression of E-cadherin makes cancer cells break away from primary lesions in non-small cell lung cancer. Moreover, E-cadherin expression is negatively correlated with histological grade, lymph node metastasis and differentiation in non-small cell lung cancer.The absence of E-cadherin-mediated cell-cell contact is regarded to be permissive for the induction of EMT. In the presence of E-cadherin-mediated cell-cell contact, TGF-β1 could not induce EMT. Surprisingly, when E-cadherin is over-expressed, mesenchymal-epithelial transition of cancer cells is induced. All these findings support that E-cadherin deeply impacts on the prognosis of cancer. Here, our results showed that RBP2 siRNA could up-regulate the expression of E-cadherin in both types of cancer cells, but it had greater effect in lung squamous cancer cells. Our report provides suggestion that the RBP2-targeted drugs have potential to improve the prognosis of lung squamous cancer and esophageal squamous cancer, and they might display better efficacy in clinical treatment of lung squamous cancer than esophageal squamous cancer.Bothe other reports and our study indicate that RBP2 is widely overexpressed in many types of cancers, it deeply impacts the proliferation, migration, metastasis and durg resistance of cancer cells. Therefore, RBP2 may be a potential target for anti-lung cancer therapy. Moreover, another new founding provides some theoretical guidance for the clinical application of RBP2-targeted drugs.