Crizotinib resistance reversal in ALK-positive lung cancer through zeolitic imidazolate framework-based mitochondrial damage.

Crizotinib (CRZ), one of anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), has emerged as a frontline treatment for ALK-positive (ALK+) lung adenocarcinoma. However, the overexpression of P-glycoprotein (P-gp, a mitochondrial adenosine triphosphate (ATP)-dependent protein) in lung adenocarcinoma lesions causes multidrug resistance (MDR) and limits the efficacy of CRZ treatment. Herein, a mitochondria-targeting nanosystem, zeolitic imidazolate framework-90@indocyanine green (ZIF-90@ICG), was fabricated to intervene in mitochondria and overcome drug resistance. Due to the zinc ion (Zn2+) interference of ZIF-90 and the photodynamic therapy (PDT) of ICG, this nanosystem is well suited for damaging mitochondrial functions, thus downregulating the intracellular ATP level and inhibiting P-gp expression. In addition, systematic bioinformatics analysis revealed the upregulation of CD44 in CRZ-resistant cells. Therefore, hyaluronic acid (HA, a critical target ligand of CD44) was further modified on the surface of ZIF-90@ICG for active targeting. Overall, this ZIF-90@ICG nanosystem synergistically increased the intracellular accumulation of CRZ and reversed CRZ resistance to enhance its anticancer effect, which provides guidance for nanomedicine design to accurately target tumours and induce mitochondrial damage and represents a viable regimen for improving the prognosis of patients with ALK-TKIs resistance. STATEMENT OF SIGNIFICANCE: The original aim of our research was to combat multidrug resistance (MDR) in highly aggressive and lethal lymphoma kinase-positive (ALK+) lung adenocarcinoma. For this purpose, a cascade-targeted system was designed to overcome MDR, integrating lung adenocarcinoma-targeted hyaluronic acid (HA), mitochondrion-targeted zeolitic imidazolate framework-90 (ZIF-90), the clinically approved drug crizotinib (CRZ), and the fluorescence imaging agent/photosensitizer indocyanine green (ICG). Moreover, using a "two birds with one stone" strategy, ion interference and oxidative stress induced by ZIF-90 and photodynamic therapy (PDT), respectively, disrupt mitochondrial homeostasis, thus downregulating adenosine triphosphate (ATP) levels, inhibiting MDR-relevant P-glycoprotein (P-gp) expression and suppressing tumour metastasis. Overall, this research represents an attempt to implement the concept of MDR reversal and realize the trade-offs between MDR and therapeutic effectiveness.

Tumor lymphangiogenesis index reveals the immune landscape and immunotherapy response in lung adenocarcinoma.

Background: Lymphangiogenesis (LYM) has an important role in tumor progression and is strongly associated with tumor metastasis. However, the clinical application of LYM has not progressed as expected. The potential value of LYM needs to be further developed in lung adenocarcinoma (LUAD) patients. Methods: The Sequencing data and clinical characteristics of LUAD patients were downloaded from The Cancer Genome Atlas and GEO databases. Multiple machine learning algorithms were used to screen feature genes and develop the LYM index. Immune cell infiltration, immune checkpoint expression, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and drug sensitivity analysis were used to explore the correlation of LYM index with immune profile and anti-tumor therapy. Results: We screened four lymphangiogenic feature genes (PECAM1, TIMP1, CXCL5 and PDGFB) to construct LYM index based on multiple machine learning algorithms. We divided LUAD patients into the high LYM index group and the low LYM index group based on the median LYM index. LYM index is a risk factor for the prognosis of LUAD patients. In addition, there was a significant difference in immune profile between high LYM index and low LYM index groups. LUAD patients in the low LYM index group seemed to benefit more from immunotherapy based on the results of TIDE algorithm. Conclusion: Overall, we confirmed that the LYM index is a prognostic risk factor and a valuable predictor of immunotherapy response in LUAD patients, which provides new evidence for the potential application of LYM.

Characterization of polyamine metabolism predicts prognosis, immune profile, and therapeutic efficacy in lung adenocarcinoma patients.

Background: Polyamine modification patterns in lung adenocarcinoma (LUAD) and their impact on prognosis, immune infiltration, and anti-tumor efficacy have not been systematically explored. Methods: Patients from The Cancer Genome Atlas (TCGA) were classified into subtypes according to polyamine metabolism-related genes using the consensus clustering method, and the survival outcomes and immune profile were compared. Meanwhile, the geneCluster was constructed according to the differentially expressed genes (DEGs) of the subtypes. Subsequently, the polyamine metabolism-related score (PMRS) system was established using the least absolute shrinkage and selection operator (LASSO) multivariate regression analysis in the TCGA training cohort (n = 245), which can be applied to characterize the prognosis. To verify the predictive performance of the PMRS, the internal cohort (n = 245) and the external cohort (n = 244) were recruited. The relationship between the PMRS and immune infiltration and antitumor responses was investigated. Results: Two distinct patterns (C1 and C2) were identified, in which the C1 subtype presented an adverse prognosis, high CD8+ T cell infiltration, tumor mutational burden (TMB), immune checkpoint, and low tumor immune dysfunction and exclusion (TIDE). Furthermore, two geneClusters were established, and similar findings were observed. The PMRS, including three genes (SMS, SMOX, and PSMC6), was then constructed to characterize the polyamine metabolic patterns, and the patients were divided into high- and low-PMRS groups. As confirmed by the validation cohort, the high-PMRS group possessed a poor prognosis. Moreover, external samples and immunohistochemistry confirmed that the three genes were highly expressed in tumor samples. Finally, immunotherapy and chemotherapy may be beneficial to the high-PMRS group based on the immunotherapy cohorts and low half-maximal inhibitory concentration (IC50) values. Conclusion: We identified distinct polyamine modification patterns and established a PMRS to provide new insights into the mechanism of polyamine action and improve the current anti-tumor strategy of LUAD.

Delta-like ligand 3 in small cell lung cancer: Potential mechanism and treatment progress.

Small cell lung cancer (SCLC) is one of a pathological type of lung cancer, and it is characterized by invasiveness, high malignancy and refractoriness. The mortality rate of SCLC is significantly higher than other types of lung cancer, and the treatment options for SCLC patients are limited. Delta-like ligand 3 (DLL3) is a Notch signaling ligand that plays a role in regulating the proliferation, development and metastasis of SCLC cells. Mnay studies have shown that DLL3 is overexpressed on the surface of SCLC cells, suggesting that DLL3 is a potential target for SCLC patients. A series of drug trials targeting DLL3 are underway. The Phase III clinical trials of Rova-T, a drug targeting DLL3, have not yielded the expected results. However, other drugs that target DLL3, such as AMG119, AMG757 and DLL3-targeted NIR-PIT, bring new ideas for SCLC treatment. Overall, DLL3 remains a valuable target for SCLC.

Differences between Advanced Large Cell Neuroendocrine Carcinoma and Advanced Small Cell Lung Cancer: A Propensity Score Matching Analysis.

Background: Nowadays, the characteristics and treatment of advanced pulmonary large cell neuroendocrine carcinoma (LCNEC) remain controversial. This study aimed to analyze the similarity of clinical characteristics, survival outcomes and treatment modalities between advanced LCNEC and advanced small cell lung cancer (SCLC) to provide more evidence for the study of advanced LCNEC. Methods: All SCLC and LCNEC patient data were obtained from the SEER database (2010-2019). Pearson's χ2 test was used to compare the differences in clinical characteristics. Propensity score matching (PSM) was utilized to balance the bias of the variables between patients. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify prognostic factors. KM analysis was used to calculate survival. Results: A total of 1094 patients with IV LCNEC and 20939 patients with IV SCLC were included in this study. The demographic characteristics and tumor characteristics of IV LCNEC and IV SCLC were different (p < 0.05). After PSM, the overall survival (OS) for IV LCNEC and IV SCLC was 6.0 months, the cancer-specific survival (CSS) was 7.0 months, and there was no significant difference in OS or CSS between the two groups. Risk/protective factors for OS and CSS were similar for IV LCNEC and IV SCLC patients. Survival outcomes were similar in patients with IV LCNEC and IV SCLC with different treatment modalities; chemoradiotherapy significantly improved OS and CSS in patients with IV LCNEC (9.0 months) and SCLC (10.0 months), however, radiotherapy alone did not improve survival in patients with IV LCNEC. Conclusions: These results confirmed that the prognosis and treatment modalities are similar and that advanced LCNEC could be treated as advanced SCLC, which provide new evidence for the treatment of advanced LCNEC patients.

Vasculogenic mimicry score identifies the prognosis and immune landscape of lung adenocarcinoma.

Background: Lung cancer has a high incidence and mortality rate worldwide. Vasculogenic mimicry (VM) is a specific modality of tumor angiogenesis that could potentially be a new target for tumor therapy. The purpose of this study was to explore the role of VM-related genes in assessing the prognosis and immune landscape of lung cancer. Methods: VM-related genes were obtained from previous studies, and the expression data and clinical data of lung adenocarcinoma (LUAD) patients were obtained from the TCGA database and GEO database. We performed enrichment analysis of 24 VM-related genes and screened hub genes by constructing a protein-protein interaction network and using Cytoscape software. Subsequently, we developed the VM score based on univariate Cox regression analysis and Lasso analysis and validated the VM score on the GSE72094 dataset. In addition, we constructed a nomogram based on the VM score in the TCGA cohort. Finally, we explored the correlation between the VM score and the tumor microenvironment, immune cell infiltration, immune checkpoints, and drug sensitivity. Results: Enrichment analysis revealed that VM-related genes were associated with the HIF signaling pathway and angiogenic pathway. We developed a VM score based on 3 genes (EPHA2, LAMC2 and LOXL2) in LUAD patients. Kaplan-Meier analysis showed that the VM score was associated with poor prognosis in LUAD patients. The receiver operating characteristic curve suggested that the VM score and nomogram are valid predictors for the overall survival of LUAD patients. The VM score was significantly correlated with immune cell infiltration, such as naïve B cells, neutrophils, and eosinophils, and there was a difference in the TME between the high VM score group and the low VM score group. LUAD patients in the high VM score group were more sensitive to antitumor drugs. Conclusion: In summary, the VM score developed in this study is a valuable indicator for evaluating the prognosis and immune landscape of LUAD patients. VM may be a potential target for antitumor therapy in lung cancer.

Interferon-λ contributes to endometrial receptivity.

In brief: IFN-λs participate in the fetal-maternal immune interaction, involving in immune regulation, uterine receptivity, cell migration and adhesion, and endometrium apoptosis. Our study helps to elucidate the underlying causes of the IFN-λs deficiency to spontaneous pregnancy loss in women. Abstract: Immunotherapy has been commonly used to prevent recurrent pregnancy loss in women with inadequate uterus receptivity or immunological imbalance. Many immune regulators are now identified as having crucial roles at the embryo-maternal interface. However, the clinical efficacy of immunity-related markers during the peri-implantation period remains to be explored in depth. Here, we demonstrated that endometrial expression of interferon-λ (IFN-λ), regarded as a newer class of interferons, is aberrantly lower in women who suffered from recurrent implantation failure than that in fertile control. We further uncovered genetic and biochemical evidence that IFN-λ is induced directly by estrogen in the endometrial cells, and IFN-λ pathway may play multiple roles involving the inflammatory response, uterine receptivity, cell migration, and blastocyst adhesion. Furthermore, we indicated IFN-λ lessens the sensitivity of endometrium to FASL-mediated apoptosis. In addition to uncovering this IFN-λ as a novel nonredundant regulator that participates in the fetal-maternal immune interaction, our study helps to elucidate the underlying causes of spontaneous pregnancy loss in women.

Five-hub genes identify potential mechanisms for the progression of asthma to lung cancer.

Previous studies have shown that asthma is a risk factor for lung cancer, while the mechanisms involved remain unclear. We attempted to further explore the association between asthma and non-small cell lung cancer (NSCLC) via bioinformatics analysis. We obtained GSE143303 and GSE18842 from the GEO database. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) groups were downloaded from the TCGA database. Based on the results of differentially expressed genes (DEGs) between asthma and NSCLC, we determined common DEGs by constructing a Venn diagram. Enrichment analysis was used to explore the common pathways of asthma and NSCLC. A protein-protein interaction (PPI) network was constructed to screen hub genes. KM survival analysis was performed to screen prognostic genes in the LUAD and LUSC groups. A Cox model was constructed based on hub genes and validated internally and externally. Tumor Immune Estimation Resource (TIMER) was used to evaluate the association of prognostic gene models with the tumor microenvironment (TME) and immune cell infiltration. Nomogram model was constructed by combining prognostic genes and clinical features. 114 common DEGs were obtained based on asthma and NSCLC data, and enrichment analysis showed that significant enrichment pathways mainly focused on inflammatory pathways. Screening of 5 hub genes as a key prognostic gene model for asthma progression to LUAD, and internal and external validation led to consistent conclusions. In addition, the risk score of the 5 hub genes could be used as a tool to assess the TME and immune cell infiltration. The nomogram model constructed by combining the 5 hub genes with clinical features was accurate for LUAD. Five-hub genes enrich our understanding of the potential mechanisms by which asthma contributes to the increased risk of lung cancer.

Analysis of serum exosome microRNAs in the rat model of chronic obstructive pulmonary disease.

BACKGROUND: MicroRNAs (miRNAs) play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms underlying the function of miRNAs remain to be fully understood. This study aimed to explore the profile of serum exosome-derived miRNAs in the rat model of COPD. METHODS: We established the COPD rat model by cigarette smoke exposure (CSE). The pulmonary function and morphological changes were analyzed. Serum exosomes were examined by transmission electron microscopy (TEM) and western blotting. The differentially expressed miRNAs between COPD and healthy rats were screened from exosome-derived small RNA library using bioinformatics analysis and experimentally verified in rat lung tissues by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The pulmonary function indexes in COPD rats were significantly decreased compared to control rats. The typical pathological manifestations of emphysema were observed in COPD rats. Marker proteins (CD9, CD63, and TSG101) and characteristic morphology features were detected in serum exosomes. Fifteen differentially expressed miRNAs were identified in the small RNA library. In addition, we confirmed that the expression of miR-185-5p and miR-182-5p was significantly down-regulated in the lung tissues of COPD rats compared to control rats. CONCLUSION: The expression of miR-185-5p and miR-182-5p was down-regulated in serum-derived exosomes and lung tissues of COPD rats, indicating that these two miRNAs might be involved in the development of COPD and might serve as potential biomarkers for the diagnosis of COPD.

The oncogenic role of SNRPB in human tumors: A pan-cancer analysis.

Purpose: The purpose of this study was to explore the oncogenic role of small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) in human tumors. Materials and methods: Study cases were acquired from The Cancer Genome Atlas database, the Gene Expression Omnibus database, The Human Protein Atlas, and the Clinical Proteomic Tumor Analysis Consortium. We then used the R package and several online tools to analyze and visualize the role of SNRPB across tumors. Results: We found that the expression of SNRPB was significantly increased in 28 of 33 tumors, and higher expression was observed in late pathological and TNM stages. Significantly decreased levels of SNRPB promoter methylation were observed in 12 tumors. SNRPB was found to be a risk factor for decreased overall survival in 10 tumors (p < 0.05), a risk factor for decreased disease-specific survival in 8 tumors (p < 0.05), and a risk factor for decreased progression-free interval in 7 tumors (p < 0.05). The PPI network of SNRPB and the top 100 coexpressed genes revealed that CDK1, CDC6, AURKB, CCNB1, CCNA2, and CDC45 were the most closely interacting genes across tumors. The GO and KEGG enrichment analyses revealed that SNRPB and the above genes were mainly enriched with respect to functions in cell cycle-related genetic material replication, assembly, and distribution. SNRPB was significantly associated with immune cell infiltration and the expression of immunomodulation-related genes in several but not all tumors. Conclusion and limitations: The expression of SNRPB was significantly elevated in almost all tumors, and the decreased promoter methylation level may contribute to the elevated expression of SNRPB. SNRPB may facilitate the progression of pathological and TNM stages and is a risk factor for unfavorable prognosis across tumors. However, our research was based on data obtained from public databases, without further validation of our findings at the cellular and animal levels. Therefore, further studies are needed to clarify the oncogenic mechanism of SNRPB and its potential as a therapeutic target.

The prognostic and immune infiltration role of ITGB superfamily members in non-small cell lung cancer.

PURPOSE: We aimed to explore the prognostic value of integrin-ß superfamily members (ITGBs) and their role in immune cell infiltration in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Study cases were acquired from The Cancer Genome Atlas database and The Human Protein Atlas. We then used R package and several online tools to analyze and visualize the roles of ITGBs in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). RESULTS: We found that ITGBs were differentially expressed in NSCLC. In LUAD, high expression of ITGB1 and ITGB4 was an independent risk factor for poor prognosis, and ITGB7 was an independent protective factor for overall survival; in LUSC, high expression of ITGB1, 3, 5, and 6 was associated with poor prognosis, and ITGB8 was an independent protective factor for disease-specific survival. Protein-protein interaction networks for the most associated co-expressed genes revealed the following target genes of ITGBs: PTPRC, ITGAM, and ITGB2 in LUAD and FN1, PTPRC, and ITGB2 in LUSC. Gene ontology analysis revealed that functions related to adhesion, junction, and binding were highly enriched in LUAD and LUSC. ITGBs were significantly associated with immune cell infiltration and the expression of immunomodulation-related genes in LUAD and LUSC. CONCLUSION: ITGBs were differentially expressed in NSCLC. ITGB1, 4, and 7 and ITGB1, 3, 5, 6, and 8 were found as prognostic markers in LUAD and LUSC, respectively. ITGBs were significantly associated with immune cell infiltration and the expression of immunomodulation-related genes.

Identification of N7-methylguanosine related signature for prognosis and immunotherapy efficacy prediction in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is one of the most frequent causes of tumor-related mortality worldwide. Recently, the role of N7-methylguanosine (m7G) in tumors has begun to receive attention, but no investigation on the impact of m7G on LUAD. This study aims to elucidate the significance of m7G on the prognosis and immunotherapy in LUAD. Methods: Consensus clustering was employed to determine the molecular subtype according to m7G-related regulators extracted from The Cancer Genome Atlas (TCGA) database. Survival, clinicopathological features and tumor mutational burden (TMB) analysis were applied to research molecular characteristics of each subtype. Subsequently, "limma" package was used to screen differentially expressed genes (DEGs) between subtypes. In the TCGA train cohort (n = 245), a prognostic signature was established by univariate Cox regression, lasso regression and multivariate Cox regression analysis according to DEGs and survival analysis was employed to assess the prognosis. Then the prognostic value of the signature was verified by TCGA test cohort (n = 245), TCGA entire cohort (n = 490) and GSE31210 cohort (n = 226). Moreover, the association among immune infiltration, clinical features and the signature was investigated. The immune checkpoints, TMB and tumor immune dysfunction and exclusion (TIDE) were applied to predict the immunotherapy response. Results: Two novel molecular subtypes (C1 and C2) of LUAD were identified. Compared to C2 subtype, C1 subtype had poorer prognosis and higher TMB. Subsequently, the signature (called the "m7G score") was constructed according to four key genes (E2F7, FAM83A, PITX3, and HOXA13). The distribution of m7G score were significantly different between two molecular subtypes. The patients with lower m7G score had better prognosis in TCGA train cohort and three verification cohort. The m7G score was intensively related to immune infiltration. Compared with the lower score, the higher m7G score was related to remarkable upregulation of the PD-1 and PD-L1, the higher TMB and the lower TIDE score. Conclusion: This study established a m7G-related signature for predicting prognosis and immunotherapy in LUAD, which may contribute to the development of new therapeutic strategies for LUAD.

Potential Role of GST-π in Lung Cancer Stem Cell Cisplatin Resistance.

BACKGROUND: Cancer stem cells (CSCs) are responsible for tumorigenesis, chemoresistance, and metastasis. Chemoresistance is a major challenge in the management of lung cancer. Glutathione-sulphur-transferase-π (GST-π) plays an important role in the origin and development of various types of cancer by regulating the cellular redox balance. Recent investigations have demonstrated that GST-π is associated with the chemoresistance of lung CSCs (LCSCs). However, the mechanism of GST-π in lung cancer, particularly in LCSCs, remains unclear. The present study is aimed at exploring the potential role of GST-π in stemness and cisplatin (DDP) resistance of LCSCs. Materials and methods. In the present study, lung cancer cell spheres were established using the A549 cell line, which according to our previous research, was confirmed to exhibit characteristics of stem cells. Next, GST-π protein expression, apoptosis percentage, and intracellular reactive oxygen species (ROS) concentration in A549 adherent cells and A549 cell spheres were analyzed by western blotting and flow cytometry, respectively. Finally, DDP resistance, ROS concentration, and GST-π expression in LCSCs were analyzed following the interference with GST-π using DL-buthionine-(S,R)-sulphoximine and N-acetylcysteine. RESULTS: The results revealed that GST-π was highly expressed in A549 cell spheres compared with A549 adherent cells and was associated with a decreased intracellular ROS concentration (both P < 0.05). Regulating GST-π protein expression could alter DDP resistance of LCSCs by influencing ROS. CONCLUSION: These results suggested that GST-π may be important for LCSC drug resistance by downregulating ROS levels. These findings may contribute to the development of new adjuvant therapeutic strategies for lung cancer.

Key Common Genes in Obstructive Sleep Apnea and Lung Cancer are Associated with Prognosis of Lung Cancer Patients.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with an increased risk of lung cancer. This study aimed to identify key common genes in OSA and lung cancer and explore their prognostic value in lung cancer. MATERIALS AND METHODS: Transcriptome data of OSA and lung cancer were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database, respectively. Genes associated with OSA and lung cancer were screened by weighted gene co-expression network analysis (WGCNA). Univariate and multivariate Cox regression algorithms were applied to identify key genes and construct the risk score model. Receiver operating characteristic (ROC) curves and a nomogram were performed to evaluate the prognostic value of the risk score. The screened key genes and their roles in prognosis were validated by GEO (GSE30219) analysis. RESULTS: A total of 104 common genes were screened in OSA and lung cancer by WGCNA. Modulator of apoptosis 1 (MOAP1), chromobox 7 (CBX7), platelet-derived growth factor subunit B (PDGFB), and mitogen-activated protein kinase 3 (MAP2K3) were identified as key genes by univariate and then multivariate Cox regression analyses. The risk score model was constructed on the basis of four gene signatures. ROC curves and the nomogram showed that the risk score had a high accuracy in predicting the survival of patients with lung cancer. In addition, the result of multivariate Cox regression analysis indicated that the risk score was an independent prognostic factor in lung cancer. CONCLUSION: This study constructed a unique model for predicting the prognosis of lung cancer patients on the basis of four genes common to OSA and lung cancer. These genes may also serve as candidate genes to improve our knowledge about the underlying mechanism of OSA that leads to an increased risk of lung cancer at the genetic level.

Overview of serpin B9 and its roles in cancer (Review).

Serine proteinase inhibitor B9 (serpin B9) is a member of the serine protease inhibitor superfamily, which is widely found in animals, plants and microorganisms. Serpin B9 has been reported to protect cells from the immune­killing effect of granzyme B (GrB) released by lymphocytes. In recent years, an increasing number of studies have indicated that serpin B9 is involved in tumour apoptosis, immune evasion, tumorigenesis, progression, metastasis, drug resistance and even in maintaining the stemness of cancer stem cells (CSCs). Moreover, according to clinical studies, serpin B9 has been demonstrated to be significantly associated with the development of precancerous lesions, a poor prognosis and ineffective therapies, suggesting that serpin B9 may be a potential target for cancer treatment and an indicator of cancer diagnosis; thus, it has begun to attract increased attention from scholars. The present review concisely described the structure and biological functions of the serpin superfamily and serpin B9. In addition, related research on serpins in cancer is discussed in order to provide a comprehensive understanding of the role of serpin B9 in cancer, as well as its clinical significance for cancer diagnosis and prognosis.

Role of hypoxia­inducible factor­2α in lung cancer (Review).

Hypoxia is a common phenomenon during tumorigenesis and tumour development. In recent years, studies have found that hypoxia­inducible factor (HIF)­2α, also referred to as endothelial PAS domain protein­1, plays an important role in tumours. HIF­2α is an important oncogene and a critical prognostic indicator in non­small cell lung cancer. However, no unified conclusion can be drawn concerning HIF­2α and small cell lung cancer, since few studies to date have focused on their association. An increasing number of studies have confirmed that HIF­2α is involved in tumorigenesis, cell proliferation, angiogenesis, metastasis, drug resistance and radiotherapy failure in lung cancer. Of note, HIF­2α plays a crucial role in lung cancer to maintain cancer cell stemness. Based on the importance of HIF­2α in lung cancer, HIF­2α­targeted therapy has been attracting increasing attention. Although this strategy currently appears to be promising in vitro, it has never been assessed as a therapy for lung cancer. The aim of the present review was to summarize the contribution of HIF­2α to various aspects of lung cancer, as well as its potential as targeted therapy.

Overexpression of MYBL2 promotes proliferation and migration of non-small-cell lung cancer via upregulating NCAPH.

MYB Proto-Oncogene Like 2 (MYBL2) is a highly conserved member of the Myb family of transcription factors and plays a critical role in regulating cell proliferation and survival. Here we show that overexpression of MYBL2 is frequently observed in lung adenocarcinoma (LUAD) and significantly correlates with advanced stage and poor patient survival. Knockdown of MYBL2 induced apoptosis in lung cancer cells and resulted in significant inhibition of cell proliferation, migration, and invasion. Notably, we identified Non-SMC Condensin I Complex Subunit H (NCAPH) gene as a direct target of MYBL2. NCAPH expression is highly correlated with that of MYBL2 in LUAD cases and is tightly affected by MYBL2 knockdown or overexpression in vitro. Chromatin immunoprecipitation (ChIP) assays also showed that MYBL2 directly binds to the transcription start site (TSS) of NCAPH. Moreover, we provided evidence that NCAPH functions as an oncogene in lung cancer and overexpression of NCAPH could partially rescue cell death and migration blockage induced by MYBL2 knockdown. Together, these results suggest that overexpression of MYBL2 promotes proliferation and migration of lung cancer cells via upregulating NCAPH, establishing their roles as novel prognostic biomarkers as well as potential therapeutic targets for the disease.

The Comprehensive Analyses of Genomic Variations and Assessment of TMB and PD-L1 Expression in Chinese Lung Adenosquamous Carcinoma.

The poor prognosis and fewer treatment option is a current clinical challenge for patients with lung adenosquamous carcinoma (ASC). The previous studies reported that tumor mutational burden (TMB, numbers of mutation per Megabase) is a predictor of clinical response in trials of multiple cancer types, while fewer studies assessed the relationship between TMB level and clinical features and outcomes of lung ASC. Herein, the present study enrolled Chinese patients with lung ASC. DNA was extracted from formalin-fixed paraffin-embedded tumor samples and subjected to next generation sequencing (NGS), and the 457 cancer related genes were evaluated. The results demonstrated that 95 unique genes with somatic variations were identified in the enrolled patients. The top three of high frequency gene mutations were TP53, EGFR, PIK3CA with rates of 62% (13 cases), 48% (10 cases), and 14% (3 cases), respectively. We identified TMB value was significantly correlated with pathological stages (p < 0.05) and invasion of lymph node (p < 0.05). However, TMB value was not significantly correlated to other clinicopathologic indexes, for examples, age, sex, smoking history, tumor size, as well as TP53 and EGFR mutations in lung ASC. Moreover, TMB value was associated with the overall survival (p < 0.01), but not with the relapse-free survival (p = 0.23). In conclusion, this study indicated that lung ASC with high TMB might be associated with the invasion of lymph node and short overall survival. Immunotherapy might be a promising treatment option for lung ASC patients with high TMB.

Peptide nucleic acids targeting mitochondria enhances sensitivity of lung cancer cells to chemotherapy.

Acquired resistance to chemotherapy is a major limitation for the successful treatment of lung cancer. Previously, we and others showed that formation of tumor spheres is associated with chemotherapy resistance in lung cancer cells, but the underlying mechanisms remained largely unknown. In the current study, we show that mitochondrial activity is significantly higher in A549 tumor spheres versus monolayer cells, establishing mitochondria as a putative target for antitumor therapy. To this end, we designed a peptide nucleic acids (PNAs) coupled with triphenylphosphonium (TPP) to target the displacement loop (D-loop) regulatory region of mitochondrial DNA (PNA-mito). Treatment with PNA-mito significantly disrupted mitochondrial gene expression, inhibited membrane potential and mitochondria fusion, resulting in proliferation inhibition and cell death. Consistently, in mouse xenograft models, PNA-mito could efficiently inhibit mitochondrial gene expression and block tumor growth. Treatment with a low dose of PNA-mito could significantly enhance the chemotoxicity of cisplatin (CDDP) in drug-resistant A549 tumor spheres. These results establish mitochondria-targeting PNAs as a novel strategy to enhance the accumulative therapeutic outcome of lung cancer.