Department of Thoracic Surgery, The Dingli Clinical College of Wenzhou Medical University, Wenzhou Central Hospital, Wenzhou, China.
Department of Central Lab, The Dingli Clinical College of Wenzhou Medical University, Wenzhou Central Hospital, Wenzhou, China.
BMC Cancer. 2024 Oct 29;24(1):1327. doi: 10.1186/s12885-024-13083-y.
Loss of ARID1A has been reported to drive the progression of lung adenocarcinoma, yet the underlying mechanism remains elusive. In this study, we performed secretome analysis to identify the key secreted proteins regulating lung adenocarcinoma progression. We showed that the VASN level was significantly elevated in the conditioned medium from ARID1A-depleted A549 and H1299 cells. Restoration of ARID1A in ARID1A-depleted lung adenocarcinoma cells prevented the upregulation and secretion of VASN. Clinical analysis demonstrated a negative correlation between ARID1A and VASN expression in ARID1A-mutated lung adenocarcinomas. The patients with ARID1A-mutated lung adenocarcinoma had significantly higher concentrations of serum VASN than healthy controls. Moreover, serum VASN concentrations were associated with TNM stage, lymph node metastasis, and overall survival of the patients with ARID1A-mutated lung adenocarcinoma. Functional studies indicated that VASN overexpression potentiated the proliferation, invasion, and tumorigenesis of lung adenocarcinoma cells. Antibody neutralization of VASN suppressed the aggressiveness of ARID1A-depleted lung adenocarcinoma cells both in vitro and in vivo. Addition of recombinant VASN protein promoted the proliferation and invasion of lung adenocarcinoma cells. Additionally, knockdown of Notch1 blocked the aggressive phenotype induced by recombinant VASN protein. In conclusion, our data uncover the role of VASN in mediating the progression of ARID1A-depleted lung adenocarcinoma and highlight VASN as a promising therapeutic target for this disease.
ARID1A 的缺失已被报道可驱动肺腺癌的进展，但潜在的机制仍难以捉摸。在这项研究中，我们进行了分泌组分析，以鉴定调节肺腺癌进展的关键分泌蛋白。我们发现，ARID1A 缺失的 A549 和 H1299 细胞的条件培养基中 VASN 的水平显著升高。在 ARID1A 缺失的肺腺癌细胞中恢复 ARID1A 可防止 VASN 的上调和分泌。临床分析表明，在 ARID1A 突变的肺腺癌中，ARID1A 和 VASN 的表达呈负相关。ARID1A 突变的肺腺癌患者的血清 VASN 浓度明显高于健康对照组。此外，血清 VASN 浓度与 ARID1A 突变的肺腺癌患者的 TNM 分期、淋巴结转移和总生存率相关。功能研究表明，VASN 过表达增强了肺腺癌细胞的增殖、侵袭和致瘤性。VASN 抗体中和抑制了体外和体内 ARID1A 缺失的肺腺癌细胞的侵袭性。添加重组 VASN 蛋白促进了肺腺癌细胞的增殖和侵袭。此外，Notch1 的敲低阻断了重组 VASN 蛋白诱导的侵袭表型。总之，我们的数据揭示了 VASN 在介导 ARID1A 缺失的肺腺癌进展中的作用，并强调了 VASN 作为该疾病有前途的治疗靶点。
