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This study investigated the inhibitory effects of lncRNA HLA Complex Group 11 (HCG11) on non-small cell lung cancer (NSCLC) and the molecular mechanisms. Bioinformatics analysis was conducted to determine the downstream targeted gene miR-17-5p/p21 and predict their binding sites. qRT-PCR and Western blot were used to detect expression levels, and dual luciferase and RIP assays were adopted to verify binding relationship. The lncRNA HCG11/miR-17-5p/p21 axis was found to regulate drug resistance, proliferation, apoptosis, and cell cycle of A549 and A549-Gemcitabine (GEM) cells. HCG11 acted as a ceRNA binding to miR-17-5p, which repressed p21 expression in turn. In vivo experiments demonstrated that HCG11 hindered tumor growth. Therefore, lncRNA HCG11, by targeting the miR-17-5p/p21 axis, suppressed GEM resistance and malignant progression of NSCLC cells. This study provides a reference for investigating the potential value of lncRNA HCG11 in the diagnosis of NSCLC and finding potential targets against clinical chemotherapeutic resistance in NSCLC. [ABSTRACT FROM AUTHOR]

Afatinib, a second-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been approved as EGFR, HER2, HER3 and HER4 inhibitor for non-small cell lung cancer (NSCLC) treatment. However, acquired resistance to afatinib has been found in most EGFR mutant NSCLC patients. Bladder cancer associated transcript 1 (BLACAT1) is a novel long non-coding RNAs (lncRNA) that play a functional role as an oncogenic lncRNA and is associated with chemoresistance. We aimed to identify the role of BLACAT1 in afatinib-resistant NSCLC and underlying mechanisms. Afatinib-resistant NSCLC cells were established. MTT assay, colony formation assay, apoptosis analysis, qRT-PCR and western blot analysis, immunohistochemistry, and in vivo study were carried out. BLACAT1 was up-regulated in afatinib-resistant NSCLC cells. Knockdown of BLACAT1 reversed the resistance of afatinib to NSCLC cells by modulating STAT3 signalling. The results provided a potential strategy for afatinib-resistant NSCLC by targeting BLACAT1. [ABSTRACT FROM AUTHOR]

Abstract Non-small cell lung cancer (NSCLC) patients harboring EGFR mutation who initially respond to EGFR-TKI will gradually develop acquired resistance. There is still a challenge to treat EGFR-TKI resistant NSCLC patients. Polyphyllin I (PP I), a steroidal saponin isolated from Paris polyphylla., has been exhibited antitumor activities against various carcinomas. However, its mechanism in treating EGFR-TKI resistant NSCLC has not been well elucidated. In this study, we found that PP I suppressed the cell viability and induced apoptosis of gefitinib-resistant NSCLC cells and xenograft models. These therapeutic efficacies were associated with down-regulated level of MALAT1, leading to inactivation of STAT3 signaling pathway. The cell viability inhibition and apoptosis inducing in gefitinib-resistant NSCLC triggered by PP I were abolished by MALAT1 overexpression, while the cell viability inhibition and apoptosis inducing triggered by PP I were potentiated by MALAT1 knockdown. These findings suggest that, in vitro and in vivo, PP I inhibits the viability and induces apoptosis of gefitinib-resistant NSCLC by down-regulating MALAT1 and inactivating STAT3 signaling pathway. Thus, PPI could serve a promising therapeutic agent for the treatment of gefitinib-resistant NSCLC. Highlights • There is still a challenge to treat EGFR-TKI resistant NSCLC. • PP I suppressed the cell viability and induced apoptosis of drug-resistant NSCLC. • PP I might down-regulate MALAT1 expression and inactivate STAT3 signaling pathway. • PP I could serve a promising therapeutic agent for gefitinib-resistant NSCLC. [ABSTRACT FROM AUTHOR]

MALAT1 has been implicated in tumor progression. But the mechanism and role underlying MALAT1 in non-small cell lung cancer (NSCLC) cell resistance to gemcitabine (GEM) remain rarely understood. Through bioinformatics analysis, we predicted MALAT1/miR-27a-5p/PBOV1 regulatory axis and constructed GEM resistant A549/GEM cell line, and A549 was the parent cell line. qRT-PCR was utilized to assess MALAT1, miR-27a-5p and PBOV1 expression in A549 and A549/GEM cells. MTT method and colony formation assay were utilized to measure cell viability and cell proliferation. Flow cytometry was conducted to assess cell cycle and cell apoptosis. Wound healing and Transwell assays were conducted to measure cell migratory and invasive potentials. Dual-luciferase reporter gene assay and RNA immunoprecipitation were utilized to identify the targeted relationship between MALAT1 and miR-27a-5p, and the former assay was also utilized to determine the targeted relationship between miR-27a-5p and PBOV1. The impacts of MALAT1/miR-27a-5p/PBOV1 on tumor growth and GEM resistance of NSCLC cells in vivo were validated by using the tumor xenograft model. MALAT1 was observed to be highly expressed in tissues and cells of GEM resistant patients. Forced level of MALAT1 could markedly enhance A549 cell resistance to GEM, but this impact could be weakened by silencing MALAT1. MALAT1 downregulated miR-27a-5p level. PBOV1 was the target of miR-27a-5p and could significantly enhance GEM resistance of NSCLC cell. MALAT1 facilitated tumor growth in vivo via targeting miR-27a-5p/PBOV1 and enhanced resistance of NSCLC cells to GEM. MALAT1/miR-27a-5p/PBOV1 axis was implicated in NSCLC cell resistance to GEM. We deepened our understanding about how MALAT1 enhanced NSCLC cell resistance to GEM and provided development of therapeutic strategy for NSCLC with a possible target. • LncRNA MALAT1 was associated with gemcitabine resistance in NSCLC cells. • LncRNA MALAT1 targeted miR-27a-5p in NSCLC. • PBOV1 was the direct target of miR-27a-5p in NSCLC. • LncRNA MALAT1 enhanced non-small cell lung cancer cell resistance to gemcitabine by directly affecting miR-27a-5p/PBOV1 axis. [ABSTRACT FROM AUTHOR]

• Silencing TRIM66 hindered cell malignant phenotype of non-small cell lung cancer; • TRIM66 interacted with MMP9 in non-small cell lung cancer; • MMP9 activated TGF-β/SMAD pathway; • TRIM66/MMP9/TGF-β/SMAD axis promoted non-small cell lung cancer progression. To investigate regulatory function and underlying mechanism of TRIM66 in non-small cell lung cancer (NSCLC). TRIM66 and MMP9 expression in NSCLC cells and tissues was assayed via qRT-PCR and western blot. CCK-8, colony formation, Transwell and flow cytometry assays were conducted to measure cell functional alternations in NSCLC. Western blot was employed to measure expression as well as phosphorylation levels of epithelial-mesenchymal transition-(EMT) and TGF-β/SMAD pathways-related proteins. Co-immunoprecipitation (Co-IP) assay was done to probe interaction between TRIM66 and MMP9. Xenograft in vivo experiment and tumor metastasis model in nude mice were utilized to investigate effects of TRIM66 on tumor growth of NSCLC. TRIM66 and MMP9 were conspicuously highly expressed in NSCLC cells and tissues. High TRIM66 level was markedly correlated with metastasis. Silencing TRIM66 prominently repressed the proliferation, migration and invasion of transfected cells, while inducing cell apoptosis. Whereas forced expression of TRIM66 exerted the opposite effect. The aberrant expression of TRIM66 modulated EMT pathway. TRIM66 also regulated MMP9 expression, and the interaction between them was validated by Co-IP assay. Overexpression of MMP9 could activate TGF-β/SMAD pathway. Rescue experiments manifested that si-MMP9 or SB431542 could partially reverse phenotypes induced by TRIM66. In vivo experiments revealed that silencing TRIM66 could hamper NSCLC tumor growth and metastasis. TRIM66 and MMP9 were up-regulated in NSCLC. TRIM66 facilitated the malignant progression of NSCLC through modulating MMP9-mediated TGF-β/SMAD pathway. [ABSTRACT FROM AUTHOR]

Lung cancer has a higher incidence and mortality rate than other cancers, and over 80% of lung cancer cases were classified as non-small-cell lung cancer (NSCLC). TRIM66 is one of the crucial members of TRIM, which has a deep connection with the behavior of various malignant tumors. But it remains uncertain regarding its exact function and underlying mechanism in NSCLC. In our study, qRT-PCR and Western blot were employed to validate that TRIM66 was overexpressed in NSCLC. The migration, invasion, and epithelial-mesenchymal transformation (EMT) progression of NSCLC cells were determined by Western blotting and Transwell experiments after knocking down TRIM66, and it was found that knockdown TRIM66 inhibited the migration, invasion, and EMT processes of NSCLC cells. Next, the binding relationship between TRIM66 and MMP9 was verified by Co-IP assay. After determining the interaction between them, rescue assays showed that overexpression of MMP9 was capable to promote the migration, invasion, and EMT of NSCLC cells. However, the transfection of si-TRIM66 could reverse this facilitating effectiveness. To sum up, we concluded that by targeting MMP9, TRIM66 could exert a cancer-promoting role in the progression of NSCLC cells. [ABSTRACT FROM AUTHOR]