| Background:Lung cancer is a malignant tumor originating from the bronchial mucosa or lung glands of the lung.At present,the morbidity and mortality are extremely high and on the rise year by year worldwide[1].According to histopathological classification,lung cancer can be divided into small cell lung cancer and non-small cell lung cancer,among which non-small cell lung cancer（NSCLC）is divided into squamous cell carcinoma,adenocarcinoma and large cell carcinoma,accounting for about 85%of all lung cancer types[2].The diagnosis stage of most patients has been in the stageⅢorⅣ,that is,the middle and late stage,and the cancer cells have metastasized in multiple places and are no longer suitable for surgical treatment[3].However,the clinical use of radiotherapy combined with chemotherapy has limitations and many side effects,so it is not the first choice therapy.Despite rapid advances in science,technology and medical treatment in the last decade,the survival of patients with non-small cell lung cancer is still low,and future screening for lung cancer may depend on tumor biomarkers.In recent years,carcinoembryonic antigen（CEA）as a tumor marker has received great attention.CEA is a glycoprotein on the surface of carcinoembryonic cells,which can be used as an indicator of diagnosis,treatment and prognosis of cancer.CEA increases in digestive tract tumors,breast cancer,carcinoid cancer,liver cancer and other tumor tissues,which is also one of the earliest tumor markers used in the detection of NSCLC and can be used as an independent prognostic factor of NSCLC[4].In recent years,great progress has been made in the effect of traditional Chinese medicine on non-small cell lung cancer.In the treatment of lung cancer by traditional Chinese medicine,based on the principles of"supporting right as the foundation,dispelling evil as the standard and treating both symptoms and root causes",symptoms of lung cancer patients have been significantly improved,discomfort has been reduced and overall quality of life has been improved[5].At present,most studies believe that its mechanism is mainly to improve the immune function of the body,affect the cell cycle,and induce the apoptosis of tumor cells[6].Therefore,it is urgent to discuss the anti-lung cancer mechanism of traditional Chinese medicine,so as to provide strong evidence for the clinical treatment of non-small cell lung cancer with traditional Chinese medicine.Tripterygium wilfordis is a kind of traditional Chinese herbal medicine,born in shady and wet hillside,stream side shrubbery,etc.,and distributed in Zhejiang,Hunan,Fujian and other places,widely used in the treatment of rheumatism,leprosy,eczema,scabies swollen poison[7].Triptolidenol,a kind of diterpenoid compound isolated from tripterygium wilfordii,has extensive pharmacological effects such as dispelling wind and dampness,anti-inflammatory and immunosuppression.Recently,the anticancer properties of triptolidenol have attracted wide attention.In vitro and in vivo studies have shown that triptolidenol has activity on renal cell carcinoma,prostate cancer,lung cancer,etc.A recent study has shown that the anticancer mechanism of triptolidenol is the inhibition of pro-inflammatory cytokines in the inflammatory microenvironment[8].Our research group has recently found that triptolidenol can delay the progression of cancer by inhibiting the growth and proliferation of tumor cells.It is suggested that triptolidenol may be used as an antitumor drug to improve respiratory tumors.However,whether triptolidenol has a inhibitory effect on non-small cell lung cancer and the mechanism of action remains unclear.Expression of cyclin D1（CCND1-cyclin D1）has been shown to be associated with early cancer onset and tumor progression by leading to increased anchorage-independent growth and angiogenesis of tumors through VEGF production,whose activity is required for cell cycle G1/S conversion.Mutations,amplification,and overexpression of this gene alter the course of the cell cycle and are commonly found in various tumors.Abnormal expression of this gene is also found in the pathogenesis of lung cancer,suggesting that CCND1 is a promising target for lung cancer[9].The PI3K/AKT signaling pathway has been identified as an early event in lung cancer,in part because activated members of its pathway proteins are highly expressed relative to normal lung tissues in precancerous and cancerous lung lesions[10].Purpose:To investigate the inhibitory effect of triptolidenol on the growth and proliferation of lung cancer cell A549.To elucidate the molecular mechanism of triptolidenol inhibiting the growth and proliferation of lung cancer cells by influencing CCND1.Methods:Cohort analysis and cumulative meta-analysis were used to study the effect of CEA level on prognosis of patients with lung cancer in clinical case reports.The malignant phenotype of lung cancer cells（A549）was determined by CCK8,cell colony,scratch assay and Transwell assay.Flow cytometry was used to detect the effect of triptolidenol on cell cycle of lung cancer.The specific target molecule CCND1 was determined by RNAseq sequencing.Western-blot were used to detect the difference in the expression of CCND1 in lung cancer cells before and after treatment with triptolidenol.The expressions of PI3K/AKT signaling pathway in lung cancer cells treated with triptolidenol were detected by Western-blot.Results:CEA level of patients can be used as a prognostic index to judge lung cancer survival.The growth,proliferation,migration and invasion of lung cancer cells were weakened after treatment with triptolidenol.Flow cytometry showed that the cell cycle of lung cancer A549 could be arrested in G1 phase.The expression level of CCND1 in the lung cancer cell lines treated with triptolidenol was significantly lower than that in the control group.Western blot results showed that triptolidenol inhibited the activation of PI3K/AKT signaling pathway.Conclusion:1.CEA can be used as a prognostic indicator for non-small cell lung cancer.2.Triptolidenol can inhibit the growth and proliferation of lung cancer cells and arrest the cell cycle in G1 phase.3.Triptolidenol inhibits cell migration and invasion in a concentration-dependent manner.4.Triptolidenol may inhibit the development of lung cancer by regulating the expression of CCND1.5.Triptolidenol can inhibit the growth and proliferation of lung cancer cells by inhibiting PI3K/AKT signaling pathway. |
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