LINC01133 contributes to the malignant phenotypes of non-small cell lung cancer by targeting miR-30b-5p/FOXA1 pathway.

This study aimed to explore the mechanism of action of LINC01133 in non-small cell lung cancer. LINC01133 expression in NSCLC patient tissues and cells was detected by qRT-PCR. After transfecting siRNA-LINC01133 in NSCLC cells, the proliferation and invasive migration ability of the cells were assessed via CCK-8 and Transwell assay, respectively. The sublocalization of LINC01133 in NSCLC cells was analyzed by bioinformatics prediction and nucleoplasm separation assay and RNA-FISH assay. Analysis of the binding relationship between LINC01133, FOXA1 and miR-30b-5p was all through bioinformatics website analysis, dual-luciferase reporter and RNA Pulldown assay. Functional rescue experiments confirmed the character of miR-30b-5p and FOXA1 in LINC01133 regulating the NSCLC cells biological behavior. LINC01133 high expressions were found in NSCLC tissues and cells. siRNA-LINC01133 treatment inhibited NSCLC cells malignant behavior. Mechanistically: LINC01133 promoted FOXA1 expression through adsorption binding of miR-30b-5p. Knocking down miR-30b-5p expression or up-regulating FOXA1 expression was able to reverse siRNA-LINC01133 inhibitory effect of tumor cell malignant behavior. LINC01133 promoted FOX1 expression by competitively binding miR-30b-5p, which attenuated the targeting inhibitory effect of miR-30b-5p on FOXA1 and ultimately promoted proliferation and invasive migration of NSCLC cells.

Combined pembrolizumab and bevacizumab therapy effectively inhibits non-small-cell lung cancer growth and prevents postoperative recurrence and metastasis in humanized mouse model.

Antibodies targeting the programmed cell death protein 1/programmed cell death ligand-1 (PD-1/PD-L1) pathway have dramatically changed the treatment landscape of advanced non-small cell lung cancer (NSCLC). However, combination approaches are required to extend this benefit beyond a subset of patients. In addition, it is of equal interest whether these combination therapy can be applied to neoadjuvant therapy of early-stage NSCLC. In this study, we hypothesized that combining immunotherapy with anti-angiogenic therapy may have a synergistic effect in local tumor control and neoadjuvant therapy. To this end, the effect of combination of bevacizumab and pembrolizumab in humanized mouse models was evaluated. Furthermore, we innovatively constructed a neoadjuvant mouse model that can simulate postoperative recurrence and metastasis of NSCLC to perform neoadjuvant study. Tumor growth and changes in the tumor vasculature, along with the frequency and phenotype of tumor-infiltrating lymphocytes, were examined. Additionally, in vivo imaging system (IVIS) was used to observe the effect of neoadjuvant therapy. Results showed that combination therapy could inhibited tumor growth by transforming tumor with low immunoreactivity into inflamed ('hot') tumor, as demonstrated by increased CD8+granzyme B+ cytotoxic T cell infiltration. Subsequent studies revealed that this process is mediated by vascular normalization and endothelial cell activation. IVIS results showed that neoadjuvant therapy can effectively prevent postoperative recurrence and metastasis. Taken together, these preclinical studies demonstrated that the combination of bevacizumab and pembrolizumab had a synergistic effect in both advanced tumor therapy and neoadjuvant setting and therefore provide a theoretical basis for translating this basic research into clinical applications.

ER Stress-Related Genes EIF2AK3, HSPA5, and DDIT3 Polymorphisms are Associated With Risk of Lung Cancer.

Objective: This study aimed to evaluate the associations between endoplasmic reticulum (ER) stress-related genes EIF2AK3/PERK, HSPA5/GRP78, and DDIT3/CHOP polymorphisms and the risk of lung cancer. Methods: Six single-nucleotide polymorphisms (SNPs) of EIF2AK3, HSPA5, and DDIT3 were genotyped in 620 cases and 620 controls using a MassARRAY platform. Results: The minor allele A of rs6750998 was a protective allele against the risk of lung cancer (p < 0.001), while the minor alleles of rs867529, rs391957, and rs697221 were all risk alleles that may lead to multiplied risk of the disease (rp rs867529 = 0.002; p rs391957 = 0.015; p rs697221 < 0.001). Moreover, the rs6750998-TA/AA genotypes were protective genotypes against the risk of lung cancer (p = 0.005); however, the rs867529-GC/CC, rs391957-CC, and rs697221-GA/AA genotypes were associated with elevated lung cancer risk (p rs867529 = 0.003, p rs391957 = 0.028, and p rs697221 = 0.0001). In addition, EIF2AK3-rs6750998 was associated with a decreased risk of lung cancer under dominant, recessive, and log-additive models (p < 0.05). By contrast, the EIF2AK3-rs867529 was correlated with an increased risk of the disease under dominant and log-additive models (p = 0.001). Moreover, HSPA5-rs391957 was related to an elevated risk of the disease under recessive and log-additive models (p < 0.02). DDIT3-rs697221 was identified to have a significant association with the risk of lung cancer under all three genetic models (p < 0.01). Conclusion: Our results provide new insights on the role of the ER stress-related genes EIF2AK3, HSPA5, and DDIT3 polymorphisms for lung cancer risk.

Effects of postoperative adjuvant radiotherapy on stage IIIA-N2 non-small cell lung cancer and prognostic analysis.

PURPOSE: We aimed to explore the efficacy and safety of postoperative adjuvant radiotherapy in the treatment of non-small cell lung cancer (NSCLC) (stage IIIA-N2), and to analyze the influencing factors for the prognosis of patients. METHODS: A total of 142 patients with NSCLC (stage IIIA-N2) were collected for retrospective analysis. Postoperative adjuvant radiotherapy was performed in 71 cases (Radiotherapy group), while it was not conducted in the remaining 71 cases (Control group). The survival status of patients was recorded during follow-up. Moreover, the possible influencing factors for the prognosis of patients were analyzed. RESULTS: The median survival time was 34.7±5.4 months and 31.9±4.9 months, the 5-year overall survival (OS) rate was 32.4% and 26.8%, and the 5-year progression-free survival (PFS) rate was 25.4% and 12.7%, respectively, in the Radiotherapy group and the Control group. The 5-year OS was significantly correlated with smoking history, tumor T stage, ratio of positive lymph nodes, number of cycles of postoperative chemotherapy, and whether postoperative adjuvant radiotherapy was combined. Moreover, tumor T stage, ratio of positive lymph nodes and whether adjuvant radiotherapy was combined were independent influencing factors for postoperative OS of patients. The lower tumor T stage, lower ratio of positive lymph nodes and adjuvant radiotherapy combined corresponded to the higher OS rate. CONCLUSIONS: Postoperative adjuvant radiotherapy is safe and feasible in the treatment of NSCLC (stage IIIA-N2), which can increase the survival of patients and the local control rate of tumors. Patients with a lower tumor T stage and a lower ratio of positive lymph nodes have higher survival rates.