Knockdown of SMAD3 Inhibits the Growth and Enhances the Radiosensitivity of Lung Adenocarcinoma via p21/Cell Cycle in vitro and in vivo

Background: Lung cancer is still the leading cause of cancer incidence and mortality. Radiotherapy is an effective approach for the treatment of lung adenocarcinoma. However, evidence suggests that lung adenocarcinoma easily develop tolerance to radiotherapy. Methods: RNA-Sequencing was performed to detect the changes in gene expression following knockdown SMAD3. Subcutaneous tumor formation assay was conducted to verify the effect of SMAD3 on the radiosensitivity and its regulatory mechanism in nude mice. Furthermore, based on the data from online databases and our department, we investigated the correlation between SMAD3 or p21 expression and the survival of patients using GEPIA and KMplot. Tissue microarrays was used to investigate the expression of SMAD3 and p21 in the tumor samples of 119 lung adenocarcinoma patients. Findings: We determined that knockdown of SMAD3 inhibits the growth and enhances the radiosensitivity of lung adenocarcinoma via p21/cell cycle in vitro and in vivo. Moreover, the level of SMAD3 and p21 expression was negatively correlated with survival of lung adenocarcinoma patients. Interpretations: We determined that the expression levels of SMAD3 and p21 were highly positively correlated with patients' survival as well radiotherapy outcomes. Overall, the data in this study indicated that SMAD3 was a potential indicator of prognosis and radiosensitivity as well as a target for radiotherapy and other treatments of lung adenocarcinoma. Funding Statement: This work was supported by the National Natural Science Foundation of China (Nos. 81401875, 81703023, http://www.nsfc.gov.cn/), and Youth Programme of Zhongshan Hospital, Fudan University (Grant No. 2018ZSQN45). Declaration of Interests: The authors have declared that there is no conflict of interest. Ethics Approval Statement: Animal experiment protocol was approved by the Animal Ethics Committee of Zhongshan Hospital, Fudan University. All the patients’ tissue specimens was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (B2017-052)