Lung cancer, especially lung adenocarcinoma (LUAD), is one of the most common neoplasms worldwide. However, the mechanisms underlying its initiation, development, and metastasis are still poorly understood. Destrin (DSTN) is a member of ADF/cofilin family. Its detailed biological function remains unknown, although it is reported that DSTN is involved in cytoskeleton remodeling and regulation of actin filament turnover. Recent evidence has shown that high expression of cofilin-1 is associated with invasion and poor prognosis of several types of human tumors, but the detailed mechanism is still entirely unclear, particularly in lung cancer tumorigenesis and malignancy. Here, we report that DSTN was highly expressed in a mouse lung cancer model induced by urethane and in clinical LUAD tissue samples. Its expression level was positively correlated with cancer development, as well as metastasis to the liver and lymph nodes. Consistently, it was directly associated with the poor prognosis of LUAD patients. Furthermore, we also found that DSTN promotes cell proliferation, invasion and migration in vitro, and facilitates subcutaneous tumor formation and lung metastasis via intravenous injection in vivo. Mechanically, DSTN associates with and facilitates nuclear translocation of β-catenin, which promotes epithelial-mesenchymal transition (EMT). Taken together, our results indicated that DSTN enhances lung cancer malignancy through facilitating β-catenin nuclear translocation and inducing EMT. Combined with multivariate analyses, DSTN might potentially serve as a therapeutic target and an independent prognostic marker of LUAD. Implications: This finding indicated DSTN facilitates β-catenin nuclear translocation and promotes malignancy in lung adenocarcinoma. Research.

<div>Abstract<p>Lung cancer, especially lung adenocarcinoma, is one of the most common neoplasms worldwide. However, the mechanisms underlying its initiation, development, and metastasis are still poorly understood. Destrin (DSTN) is a member of ADF/cofilin family. Its detailed biological function remains unknown, although it is reported that DSTN is involved in cytoskeleton remodeling and regulation of actin filament turnover. Recent evidence has shown that high expression of cofilin-1 is associated with invasion and poor prognosis of several types of human tumors, but the detailed mechanism is still entirely unclear, particularly in lung cancer tumorigenesis and malignancy. Here, we report that DSTN was highly expressed in a mouse lung cancer model induced by urethane and in clinical lung adenocarcinoma tissue samples. Its expression level was positively correlated with cancer development, as well as metastasis to the liver and lymph nodes. Consistently, it was directly associated with the poor prognosis of lung adenocarcinoma patients. Furthermore, we also found that DSTN promotes cell proliferation, invasion, and migration <i>in vitro</i>, and facilitates subcutaneous tumor formation and lung metastasis via intravenous injection <i>in vivo</i>. Mechanically, DSTN associates with and facilitates nuclear translocation of β-catenin, which promotes epithelial-to-mesenchymal transition (EMT). Taken together, our results indicated that DSTN enhances lung cancer malignancy through facilitating β-catenin nuclear translocation and inducing EMT. Combined with multivariate analyses, DSTN might potentially serve as a therapeutic target and an independent prognostic marker of lung adenocarcinoma.</p>Implications:<p>This finding indicates that DSTN facilitates β-catenin nuclear translocation and promotes malignancy in lung adenocarcinoma.</p></div>

<p>Supplementary Table 1. The differentially expressed proteins of normal and early - stage lung cancer tissues identified by LC-MS/MS analysis (N: normal; T: tumor).</p>

<p>Supplementary Materials and Methods</p>

<p>Supplementary Figure 1. Time-course analysis of the development of lung tumors induced by urethane in BALB/C mice and MS/MS analysis of destrin identified. Supplementary Figure 2. Validation of targeted proteins chosen by immunohistochemistry analysis. Supplementary Figure 3. Protein expression levels of Prdx5, Ctsd, Ctsh, Ctnna1, and Jup with reference to GAPDH (internal control), examined by immunoblot in the lung tissues of normal control mice and the mice at week 16 and 32 after Urethane treatment. Supplementary Figure 4. The effect of DSTN knockdown or overexpression on colony formation and migration in BEAS-2B cells. Supplementary Figure 5. Representative images of IHC staining using Ki67. Supplementary Figure 6. DSTN knockdown induces G2/M phase arrest in A549 and H1299 cells. Supplementary Figure 7. DSTN knockdown promotes apoptosis in A549 and H1299 cells. Supplementary Figure 8. The effect of DSTN knockdown or overexpression on the migration of A549 and H1299 in vitro. Supplementary figure 9. The effect of DSTN knockdown or overexpression on anchorage-independent growth of A549 and H1299 in vitro. Supplementary figure 10. The effect of DSTN knockdown or overexpression on EMT marker expression. Supplementary Figure 11. The effect of DSTN knockdown or overexpression on the adhesive ability of the A549 and H1299 cells. Supplementary Figure 12. DSTN knockdown or overexpression affects the sub-cellular localization of β-catenin in A549 and H1299 cells. Supplementary figure 13. The interaction between DSTN and β-catenin was assessed by Co-immunoprecipitation.</p>