LINC00963 promotes the malignancy and metastasis of lung adenocarcinoma by stabilizing Zeb1 and exosomes-induced M2 macrophage polarization

Abstract

Background Long intergenic non-coding RNA 00963 (LINC00963) is an oncogenic lncRNA in human cancers. However, little is known on how it impacts the pathogenesis of lung adenocarcinoma (LUAD). Methods Biological effects on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were examined by CCK-8, colony formation, EdU incorporation, transwell, and immunofluorescence assays, respectively. Macrophage polarization was evaluated by flow cytometry. Ubiquitination of Zeb1 was examined by co-immunoprecipitation. The location of LINC00963 in LUAD tissues and cell lines was tested by FISH assay. The LINC00963/HNRNPA2B1/Siah1 mRNA complex interaction was verified using RNA pull-down and immunoprecipitation assays. The exact roles of LINC00963 were further validated in metastasis and xenograft models. Results Higher LINC00963 expression in LUAD patients positively correlated with shorter overall survival, higher stages, and metastasis. LINC00963 mainly localized in the cytoplasm and aggravated malignant phenotypes of LUAD cells in vitro and metastasis in vivo. Mechanistically, LINC00963 directly interacted HNRNPA2B1 protein to trigger the degradation of Siah1 mRNA, which inhibited the ubiquitination and degradation of Zeb1. Moreover, exosomal LINC00963 derived from LUAD cells induced M2 macrophage polarization and promoted LUAD growth and metastasis. Conclusion By stabilizing Zeb1 in cancer cells and delivering exosomes to induce M2 macrophage polarization, LINC00963 promoted the malignancy and metastasis of LUAD. Targeting LINC00963 may become a valuable therapeutic target for LUAD.

Exosomal Non-Coding RNAs: Novel Regulators of Macrophage-Linked Intercellular Communication in Lung Cancer and Inflammatory Lung Diseases

“…LINC00963 expression is higher in lung adenocarcinoma tissues than that in normal lung tissues. Lung cancer cell-derived exosomal LINC00963 potentiates lung cancer growth via stimulating M2 macrophage polarization in vivo [ 82 ]. In summary, lung cancer cell-derived exosomal lncRNAs can act as ceRNAs to repress miRNA inhibitory effects on targeted genes, eventually influencing macrophage polarization.…”

Exosomes: Diagnostic and Therapeutic Implications in Cancer

“…M2 macrophage-derived exosomal miR-193b-3p enhances the proliferation of pancreatic cancer cells by decreasing the expression of the tripartite motif containing 62 (TRIM62) [ 77 ]. Exosomal LINC00963 of lung cancer cells enhances the metastatic potential of lung cancer cells by decreasing the expression of seven in absentia homolog 1 (SIAH1) while increasing the zinc finger E-box-binding homeobox 1 (ZEB1) expression level [ 78 ]. Altogether, these reports suggest that targeting these miRNAs could suppress cancer initiation and progression by inhibiting cellular interactions.…”

“…In particular, mimics or inhibitors could be used in combination with chemotherapeutic drugs to overcome anticancer drug resistance. Table 2 [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ] and Figure 3 show the roles played by exosomal non-coding RNAs in cancer progression and anticancer drug resistance.…”

“…Plasma exosomal lnc-SNAPC5-3:4 is significantly upregulated when anlotinib treatment is effective in patients with non-small cell lung cancers (NSCLCs) [ 96 ]. High levels of LINC00963 can predict a poor prognosis of patients with lung cancer [ 78 ]. LncRNAs—such as AL355353.1, AC011468.1, and AL354919.2—are upregulated in bladder cancer tissues [ 97 ].…”

“… Diverse roles of exosomal non-coding RNAs. Exosomal miRNAs play important roles in cancer progression/metastasis [ 74 , 75 , 76 , 77 , 78 , 79 , 80 ], immune suppression [ 76 ], and M2 macrophages polarization [ 78 ]. Hollow arrows denote the direction of the reaction.…”