LIMS2 regulates lung adenocarcinoma progression and suppresses the activation of cancer-associated fibroblast.

Lung cancer is a highly malignant tumor and prone to recurrence and metastasis. Adenocarcinoma is the most common subtype. LIM zinc finger domain containing 2 (LIMS2) was reported to inhibit growth and metastasis of several tumors, while its role in lung adenocarcinoma remains unclear. This study aims to expound the function of LIMS2 in lung adenocarcinoma. The analysis from medical databanks showed that LIMS2 was lowly expressed in lung adenocarcinoma specimens, compared with the normal lung tissues, and our clinical data demonstrated that LIMS2 expression was associated with TNM stage of lung adenocarcinoma patients. Gain- and loss-of-function experiments revealed that LIMS2 suppressed proliferation, invasion, migration, epithelial-mesenchymal transition of lung adenocarcinoma cells, delayed xenograft and orthotopic growth, and blocked distant metastasis and lymph infiltration in nude mice. The medium supernatant from LIMS2-overexpressed lung adenocarcinoma cells intercepted the activation of fibroblasts from lung cancer. The co-IP results demonstrated that an E3 ubiquitin ligase ring finger and CHY zinc finger domain containing 1 (RCHY1) interacted with LIMS2, and mediated its K48 ubiquitination and degradation. LIMS2 overexpression reversed the promoting effects of RCHY1 on proliferation, migration and lung cancer-fibroblast activation of lung adenocarcinoma cells. In conclusion, decreased LIMS2 may mediate the tumor-promoting role of RCHY1 in lung adenocarcinoma cells. Implications: These findings may provide novel diagnostic markers and therapeutic targets for lung adenocarcinoma in clinic.