A pancancer analysis of the oncogenic role of cyclin B1 (CCNB1) in human tumors.

Aberrant levels of the G2/M cyclin cyclin B1 (gene CCNB1) have been associated with multiple cancers; however, the literature lacks a focused and comprehensive analysis of the regulation of this important regulator of cell proliferation in cancer. Through this work, we performed a pancancer analysis of the levels of CCNB1 and dissected aspects of regulation and how this correlates with cancer prognosis. We comprehensively evaluated the expression and promoter methylation of CCNB1 across 38 cancers based on RNA sequencing data obtained from the Cancer Genome Atlas (TCGA). The correlation of CCNB1 with prognosis and the tumor microenvironment was explored. Using lung adenocarcinoma data, we studied the potential upstream noncoding RNAs involved in the regulation of CCNB1 and validated the protein levels and prognostic value of CCNB1 for this disease site. CCNB1 was highly expressed, and promoter methylation was reduced in most cancers. Gene expression of CCNB1 correlated positively with poor prognosis of tumor patients, and these results were confirmed at the protein level using lung adenocarcinoma. CCNB1 expression was associated with the infiltration of T helper cells, and this further correlated with poor prognosis for certain cancers, including renal clear cell carcinoma and lung adenocarcinoma. Subsequently, we identified a specific upstream noncoding RNA contributing to CCNB1 overexpression in lung adenocarcinoma through correlation analysis, expression analysis and survival analysis. This study provides a comprehensive analysis of the expression and methylation status of CCNB1 across several forms of cancer and provides further insight into the mechanistic pathways regulating Cyclin B1 in the tumorigenesis process.

The change of eosinophils in the perioperative period is significantly associated with the prognosis in patients with lung cancer.

Background: This research focuses on the relationship between the changes in peripheral blood eosinophils (PBEs) perioperatively and the prognosis of lung cancer. Methods: The study included 414 lung cancer patients. These patients were divided into the DOWN (186 patients) and UP (209 patients) groups according to perioperative changes in PBEs. Furthermore, overall survival was compared based on pathological stage, pathological type, tumor location, age and sex. Furthermore, the authors analyzed the prediction of PBEs on the prognosis of chemotherapy. Results: The results showed that lung cancer patients in the DOWN group had a better prognosis (p = 0.0121; 95% CI: 0.6915 [0.5184-0.9224]), and the DOWN group patients with normal postoperative PBEs had a better prognosis (p = 0.0115; 95% CI: 0.6721 [0.4938-0.9148]). Conclusion: Lung cancer patients whose postoperative PBEs were lower than preoperative PBEs had a better prognosis.

Hypoxia-associated prognostic markers and competing endogenous RNA coexpression networks in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common form of non-small cell lung cancer (NSCLC). Hypoxia has been found in 50-60% of locally advanced solid tumors and is associated with poor prognosis in various tumors, including NSCLC. This study focused on hypoxia-associated molecular hallmarks in LUAD. Fifteen hypoxia-related genes were selected to define the hypoxia status of LUAD by ConsensusClusterPlus based on data from The Cancer Genome Atlas (TCGA). Then, we investigated the immune status under different hypoxia statuses. Subsequently, we constructed prognostic models based on hypoxia-related differentially expressed genes (DEGs), identified hypoxia-related microRNAs, lncRNAs and mRNAs, and built a network based on the competing endogenous RNA (ceRNA) theory. Two clusters (Cluster 1 and Cluster 2) were identified with different hypoxia statuses. Cluster 1 was defined as the hypoxia subgroup, in which all 15 hypoxia-associated genes were upregulated. The infiltration of CD4+ T cells and Tfh cells was lower, while the infiltration of regulatory T (Treg) cells, the expression of PD-1/PD-L1 and TMB scores were higher in Cluster 1, indicating an immunosuppressive status. Based on the DEGs, a risk signature containing 7 genes was established. Furthermore, three differentially expressed microRNAs (hsa-miR-9, hsa-miR-31, hsa-miR-196b) associated with prognosis under different hypoxia clusters and their related mRNAs and lncRNAs were identified, and a ceRNA network was built. This study showed that hypoxia was associated with poor prognosis in LUAD and explored the potential mechanism from the perspective of the gene signature and ceRNA theory.

Development and validation of nomograms based on clinical characteristics and CT reports for the preoperative prediction of precise lymph node dissection in lung cancer.

OBJECTIVE: To develop and validate nomograms for preoperative prediction of precision lymph node (LN) dissection in lung cancer. PATIENTS AND METHODS: The prediction models of each group LNs (LNx) were developed in a primary cohort that consisted of 1380 patients with clinicopathologically confirmed lung cancer. Clinical characteristics and CT reports were extracted. Patients with LNx dissection were divided into training cohort and testing cohort. Nomograms were built through univariate and multivariate regression analysis in the training cohort and internally verified in the testing cohort. The accuracy of the models was verified by constructing survival analysis in patients without LNx dissection. RESULTS: Due to the lack of sufficient patients for LN1, 8, 13, a total of 10 nomograms were constructed in this study, including LN-2 âˆ¼ 7, 9 âˆ¼ 12. According to the nomogram of each group LN, the most common independent risk factors predicting LN status were CT-reported lymphadenectasis, tumor diameter and location, and the others include age, gender, and whether there were multiple nodules, etc. All models showed good discrimination, with the average C-index of 0.738 in the training cohort and 0.707 in the testing cohort. Survival analysis in patients without LNx dissection all showed the high accuracy of each nomogram to predict LN metastasis status and TNM staging. CONCLUSION: We constructed nomograms to predict the metastasis status of each group of lymph nodes based on clinical characteristics and CT reports. Surgeons can accurately determine the extent of lymph node dissection in patients with lung cancer based on our nomogram models before surgery.

Optimum immunotherapy method according to PD-L1 expression in advanced lung cancer: a network meta-analysis.

Aim: To compare the survival of advanced lung cancer patients treated with immune checkpoint inhibitors in different PD-L1 expression. Methods: We performed a network meta-analysis based on 25 trials involving 12,224 patients with different PD-L1 expression levels. Results: The results showed platinum-based chemotherapy plus pembrolizumab or nivolumab and ipilimumab was associated with the best survival rates for patients with <1% PD-L1 expression, while only platinum-based chemotherapy plus pembrolizumab produced better survival than chemotherapy in patients with 1-49% PD-L1 expression. As for patients with ≥50% PD-L1 expression, platinum-based chemotherapy plus pembrolizumab/atezolizumab and pembrolizumab/cemiplimab monotherapy were associated with better survival than chemotherapy. Conclusion: These results provide reference for selecting the optimum immunotherapy method based on the expression of PD-L1 in patients with advanced lung cancer.

Plain language summary Lung cancer has a high incidence and mortality rate, and there are many treatment strategies, including surgery, chemotherapy, targeted therapy and immunotherapy. The emergence of immunotherapy has effectively improved the treatment effect of lung cancer, but different immunotherapy strategies and drugs have inconsistent efficacy in different patients. In this study the expression of PD-L1 was used to differentiate patients, and the survival difference of patients receiving different immunotherapy strategies was explored through statistical methods. This study may help clinicians choose the best immunotherapy methods and drugs for different patients. Systematic review registration: PROSPERO CRD42020186947.

AGTR1 Inhibits the Progression of Lung Adenocarcinoma.

PURPOSE: The occurrence and development of lung adenocarcinoma (LUAD) are related to many factors. Multiple researches showed that the renin-angiotensin system (RAS) plays an important role in lung cancer. This research mainly focuses on angiotensin II receptor 1 (AT1R) encoding gene AGTR1, an important part of the RAS. METHODS: We comprehensively evaluated the expression of AGTR1 in pan-cancer based on RNA sequencing data obtained from The Cancer Genome Atlas (TCGA). We explored the correlation of AGTR1 with clinicopathological features, prognosis and tumor microenvironment in LUAD. We also explored the mechanism through enrichment analysis and verified it with cell lines and tissue samples. RESULTS: We found that AGTR1 was less expressed in most tumors and related to prognosis based on the TCGA database. To further explore its mechanism, we mainly focused on LUAD. Combined with the verification results in the GEO database, AGTR1 was associated with a better prognosis in LUAD. High expression of AGTR1 was associated with less lymph node metastasis (P=0.007) and MET mutation (P=0.019). High expression of AGTR1 was related to the anti-tumor immune microenvironment with high infiltration of B cells, myeloid dendritic cells, monocytes, and low infiltration of myeloid-derived suppressor cells (all P<0.05). Enrichment analysis and in vitro verification results showed that AGTR1 was likely to play a role in LUAD through the PI3K/AKT3 pathway. Finally, we verified the above results through tissue samples and the construction of AGTR1 overexpressing cells. CONCLUSION: AGTR1 inhibits the progression of lung adenocarcinoma through the PI3K/AKT3 pathway.

Co-expression network analysis identified KIF2C in association with progression and prognosis in lung adenocarcinoma.

Lung cancer is a malignant tumor with high morbidity and mortality, of which 80% is non-small cell lung cancer (NSCLC). And lung adenocarcinoma (LUAD) is the most important and common subtype in the NSCLC. In current study, the microarray data GSE31210 containing LUAD (n= 226) and normal lung tissue (n= 20) was analyzed to identify 965 differentially expressed genes, on which weighted gene co-expression network analysis was performed. Finally, it was confirmed that there was a significant correlation between brown module and LUAD stage. In the significant module, a total of 54 network hub genes were identified, and six of them were also identified as hub genes of the protein-protein interaction network. In validation, KIF2C showed a higher correlation with disease stage than other hub genes (p< 0.001, R2 = 0.955). Functional enrichment suggests that KIF2C is associated with cell mitosis and cell cycle. Combined with clinicopathological parameters, we found that the high expression of KIF2C is closely related to the relapse and tumor stage of LUAD. Survival analysis showed a significant reduction in overall survival in LUAD patients with high expression of KIF2C. Gene set enrichment analysis (GSEA) also showed that the "cell cycle signaling pathway" and "P53 related pathway" were significantly enriched in LUAD samples with high expression of KIF2C (FDR < 0.05). In conclusion, based on the co-expression analysis, KIF2C was identified in the association with progression and prognosis of LUAD, which might refer a poor prognosis probably by regulating cell cycle signaling pathway.

Interaction of estrogen receptor ß5 and interleukin 6 receptor in the progression of non-small cell lung cancer.

Numerous studies have shown that the estrogen receptor beta (ERß) and interleukin 6 receptor (IL-6R) had interaction in many tumors, including lung cancer. Previous studies found that ERß5 exhibits a different biological function compared with the other subtypes of ERß. Therefore, this study mainly explores the interaction between ERß5 and IL-6R in the progression of lung cancer. We found that the expression of ERß5, IL-6 and glycoprotein 130 (GP130) were significantly increased (P < 0.001) and the 5-year survival rate with the co-expression of ERß5 and GP130 is significantly lower (P = 0.0315) in non-small cell lung cancer (NSCLC) patients. The cell proliferation, invasion, and cell cycle were markedly increased, and the cell apoptotic was markedly inhibited with the concurrent action of ERß5 and IL-6 in A549 cells (P < 0.05). In addition, the expression of ERß5, GP130, p-AKT, and p-44/42 MAPK was also significantly increased in A549 cells (P < 0.05). These results indicate that ERß5 and GP130 can synergistically promote the progression of NSCLC and maybe combined as an independent prognostic factor in patients. In addition, these results also provide a theoretical basis for the combined targeting therapy of ERß5 and GP130 in NSCLC.

Oestrogen receptor ß5 and epidermal growth factor receptor synergistically promote lung cancer progression.

Oestrogen receptor beta (ERß) and epidermal growth factor receptor (EGFR) pathway can synergistically promote the proliferation, invasion, and metastasis of non-small-cell lung cancer (NSCLC) cells. ERß has five subtypes, and the selective splicing of exon 8 in ERß5 transcription translational phase makes its biological function different from other subtypes. The following study investigates whether ERß5 interacts with EGFR pathway in lung cancer. Briefly, we found that the overexpression of ERß5 and EGFR is associated with poor prognosis and decreased overall survival in NSCLC patients. Furthermore, the effects of ERß5 and EGFR on cell biological behaviour were investigated in vitro. These results indicated that the combination of ERß5 and EGF induces cell proliferation and invasion, while the combination of ERß5 and Gefitinib (EGFR inhibitors, Gef) induces cell apoptosis and promotes cell mitosis in A549 cell line. In addition, the combination of ERß5 and EGF increases the expression of ERß5, EGFR, and p-ERK1/2 in lung cancer cells. To sum up, the obtained results suggest that ERß5 and EGFR synergistically promote the progression of lung cancer by activating MEK/ERK signalling pathway, which provides a theoretical basis for more accurate combined targeted therapy.