The Role Of Cripto-1 And PI3K/AKT/mTOR In Cervical Cancer

Epidemiological data show that cervical cancer as the fourth most common malignancy of women, causing high morbidity and mortality every year. By 2015, there has been at least 12900 new cases in the US, and more than 4100 women died of it. The number becomes higher when it comes to the undeveloped countries in Asia and Africa. The development of cervical cancer is a continuous process:When the normal cervical epithelium suffered human papilloma virus infection, cells become poorly differentiated, dysplasia and disordered, which lead to cervical intraepithelial neoplasia and finally cancer. As the screening method developed, advanced cervical cancer declined. However, there is still an urgent need for an effective and low toxicity treatment for the unsatisfactory efficacy from the traditional methods. And here comes the molecularly targeted therapy.Crypto-1, also called TDGF-1, was named for its first isolation from human NTERA-2 teratocarcinoma cells. As a member of the epidermal growth factor-Cripto-1/FRL1/Cryptic(EGF-CFC) family, it has the typical structure of an amino-terminal signal sequence, a modified EGF-like domain, a conserved cysteine-rich domain and a Carboxy-terminal hydrophobic region. Cripto-1 not only plays an important role in the development of embryonic stem cells, it also have closely relation with the invasion, metastasis and proliferation of malignant cells. Researches have shown that Cripto-1 remains low or negative expression in normal tissues while in malignant lesions, it becomes much higher. There have been studies reveal that Cripto-1 regulates invasion and metastasis of cervical cancer cell lines through its downstream signal moleculars. Besides, researchers also found the different expression level of Cripto-1 in different cervical lesions, which demonstrates its potential significance in development of cervical cancer.As the bridge connecting extracellular signal and intracellular response, PI3K/AKT signal pathway plays an significant role in the development and treatment of malignant disease. Mammalian target of rapamyein (mTOR), as an important downstream factor, participate in the process of cell growth and proliferation. Recent studies found that the PI3K/AKT/Mtor signal pathway was excessive activated in cervical cercer, which may relates to cell cycle control and tumor proliferation. Researchers also found that mTOR can impact the effect of radiotherapy and chemotherapy.ObjectiveDetect the level of Cripto-1, p-AKT and mTOR in normal cervical epithelium(NCE), cervical intraepithelial neoplasia(CIN) and invasive carcinoma of cervix(CIN), and compare them with the relevant clinical parameters, investigate the relationship between Cripto-1 and PI3K/AKT/Mtor in the development of cervical cancer. So as to provide new clues in the prognosis and targeted therapy of cervical cancer.Material and MethodsCollect 28 cases of SCC patients,38 cases of CIN patients and 40 cases of NCE patients. Detect the expression of Cripto-1, p-AKT and mTOR by Immunohistochemistry and western blot and compare them with the relevant clinical parameters.Results1. The immunohistochemical results shows that the positive rate of Cripto-1 in SCC, CIN and NCE are 60.7%(17/28),31.6%(12/38),7.5%(3/40). The positive rate of p-AKT in the three cervical lesion groups are 78.6%(22/28),52.6%(20/38), 10%(4/40). The positive rate of mTOR in the three cervical lesion groups are 64.3%(18/28),34.2%(13/38),12.5%(5/40). There is difference of Cripto-1, p-AKT and mTOR among the three cervical lesion groups, the SCC group higher than CIN group, CIN group higher than NCE group.2. In cervical squamous cell cancer, the expression level of Cripto-1 correlates with disease staging, lymph node metastasis, regardless of the patient’s age and degree of tumor differentiation. The expression of p-AKT have no relation between patient’s age, disease staging, lymph node metastasis or degree of tumor differentiation. The expression of mTOR correlates with lymph node metastasis, regardless of patient’s age, disease staging or degree of tumor differentiation.3. In cervical squamous cell cancer, positive correlation exist between Cripto-1 and mTOR, p-AKT and mTOR, Cripto-1 and p-AKT.4. The western blot result shows that the expression of Cripto-1 in SCC, CIN and NCE are 0.82±0.44,0.37±0.12 and 0.07±0.03. The expression of p-AKT in SCC, CIN and NCE are 0.66±0.37,0.32±0.20 and 0.12±0.09. The expression of mTOR in SCC, CIN and NCE are 0.63±0.33,0.45±0.20 and 0.15±0.09. There is difference of Cripto-1, p-AKT and mTOR among the three cervical lesion groups, the SCC group higher than CIN group, CIN group higher than NCE group.Conclusion1. There is difference of Cripto-1, p-AKT and mTOR among the three cervical lesion groups, the ICC group higher than CIN group, CIN group higher than NCE group.2. In the three groups, a positive correlation exist between each two factors.3. The expression of Cripto-1, p-AKT and mTOR was closely related to the prognosis of cervical cancer.