Emerging evidences demonstrate that circular RNAs (circRNAs) are abnormally expressed in tumors and could serve as prognostic markers for cancers. However, the expression patterns and clinical implications of circRNAs in nonsmall cell lung cancer (NSCLC) remain obscure. In this study, we profiled circRNA expressions in 10 pairs of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) after ribosomal RNA-depletion and RNase R digestion to enrich circRNAs. Combining five circRNA computational programs, we found that LUAD and LUSC not only share common expression patterns, but also exhibit distinct circRNA expression signatures. Moreover, the Receiver Operating Characteristic (ROC) curve analysis indicated that hsa_circ_0077837 and hsa_circ_0001821 could serve as potential biomarkers for both LUAD and LUSC, while hsa_circ_0001073 and hsa_circ_0001495 could be diagnostic/ subtyping marker for LUAD and LUSC, respectively. Therefore, our findings highlight the important diagnostic potential of circRNAs in NSCLC.

Lung adenocarcinomas (LUAD) arise from precancerous lesions such as atypical adenomatous hyperplasia, which progress into adenocarcinoma in situ and minimally invasive adenocarcinoma, then finally into invasive adenocarcinoma. The cellular heterogeneity and molecular events underlying this stepwise progression remain unclear. In this study, we perform single-cell RNA sequencing of 268,471 cells collected from 25 patients in four histologic stages of LUAD and compare them to normal cell types. We detect a group of cells closely resembling alveolar type 2 cells (AT2) that emerged during atypical adenomatous hyperplasia and whose transcriptional profile began to diverge from that of AT2 cells as LUAD progressed, taking on feature characteristic of stem-like cells. We identify genes related to energy metabolism and ribosome synthesis that are upregulated in early stages of LUAD and may promote progression. MDK and TIMP1 could be potential biomarkers for understanding LUAD pathogenesis. Our work shed light on the underlying transcriptional signatures of distinct histologic stages of LUAD progression and our findings may facilitate early diagnosis.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in the treatment of non‐small cell lung cancer (NSCLC). Sex‐associated dimorphism in immune system response is acknowledged, but the effect of patients’ sex on efficacy of ICIs as treatment in NSCLC still remains controversial. The present study was conducted to investigate the difference in efficacy of NSCLC patients receiving immune checkpoint inhibitors according to the sex. A total of 9583 patients involved 6567 men and 3016 women with advanced lung cancer from 15 randomized controlled trials were included in this study. An overall survival (OS) benefit of immune checkpoint inhibitors was illustrated in both male (HR 0.76, 95% CI 0.71‐0.82) and female (HR 0.73, 95% CI 0.58‐0.91) patients, and a progression‐free survival (PFS) benefit was also found in both men (HR 0.67, 95% CI 0.58‐0.77) and women (HR 0.73, 95% CI 0.56‐0.95) in NSCLC. Both PD‐1/PD‐L1 inhibitors alone and PD‐1/PD‐L1 plus chemotherapy significantly improved the OS and PFS in male patients. Whereas in females, PD‐1 inhibitors or monotherapy significantly benefited the OS but not the PFS, PD‐L1 inhibitors or combination therapy significantly prolonged the PFS but not the OS. No survival benefit was found in both male and female patients from the CTLA‐4 inhibitors. The current study indicated that the magnitude of survival benefit is sex‐dependent and male patients seemed to obtain more consistent and favorable outcomes from ICIs than women patients in NSCLC.

Background: Lung cancer is the leading cause of cancer-related deaths worldwide and the prognosis remains poor. The recent introduction of the immune checkpoint inhibitor (ICI), or plus chemotherapy, both resulted in the survival benefit for patients with advanced non-small-cell lung cancer (NSCLC), but it remains unanswered which is superior. The current study aimed to estimate the comparative efficacy and safety of ICI-chemotherapy versus ICI-monotherapy in advanced NSCLC.Methods: Studies were identified by searching PubMed, Embase, and Cochrane library. The randomized controlled trials (RCTs) that ICI monotherapy or ICI plus chemotherapy compared with chemotherapy in NSCLC were included with available primary endpoints of progression-free survival (PFS), overall survival (OS), objective response rate, or treatment-related adverse events. A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.Results: A total of 20 RCTs involving 12,025 patients with NSCLC were included. Both ICI-monotherapy and ICI-chemotherapy resulted in significantly prolonged survival compared to chemotherapy and the former led to significantly longer PFS. The magnitude of survival benefits appeared to be greatest among those treated with pembrolizumab plus platinum-based chemotherapy (OS, 0.56; PFS, 0.54). Additionally, OS and PFS advantages of ICI therapies were observed in patients with NSCLC with low or high programmed cell death 1 ligand 1 (PD-L1) expression level, but not in intermediate PD-L1 TPS.Conclusions: Pembrolizumab plus platinum-based chemotherapy was recommended as the optimal first-line therapy for advanced patients with NSCLC.

Non-small cell lung carcinoma (NSCLC) is a major cancer type whose epigenetic alteration remains unclear. We analyzed open chromatin data with matched whole-genome sequencing and RNA-seq data of 50 primary NSCLC cases. We observed high interpatient heterogeneity of open chromatin profiles and the degree of heterogeneity correlated to several clinical parameters. Lung adenocarcinoma and lung squamous cell carcinoma (LUSC) exhibited distinct open chromatin patterns. Beyond this, we uncovered that the broadest open chromatin peaks indicated key NSCLC genes and led to less stable expression. Furthermore, we found that the open chromatin peaks were gained or lost together with somatic copy number alterations and affected the expression of important NSCLC genes. In addition, we identified 21 joint-quantitative trait loci (joint-QTL) that correlated to both assay for transposase accessible chromatin sequencing peak intensity and gene expression levels. Finally, we identified 87 regulatory risk loci associated with lung cancer-related phenotypes by intersecting the QTLs with genome-wide association study significant loci. In summary, this compendium of multiomics data provides valuable insights and a resource to understand the landscape of open chromatin features and regulatory networks in NSCLC.Significance: This study utilizes state of the art genomic methods to differentiate lung cancer subtypes.

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Transmembrane protein 48 (TMEM48), localized to nuclear pore complexes (NPCs), has been reported crucial for NPC assembly. Alterations in NPC members have been reported in several malignancies. The present study was aimed to elucidate the expression and biological function of TMEM48 in non-small cell lung carcinoma (NSCLC). Here, TMEM48 expression level was higher in NSCLC tissues than that in the adjacent normal tissues. Moreover, higher TMEM48 expression was correlated with a more advanced tumor stage, lymph node metastasis, bigger tumor size tumor stage, and shorter survival time. Knockdown of TMEM48 in NSCLC cell lines, A549 and H1299, inhibited cell proliferation and significantly increased cells population in G1 phase. Gene set enrichment analysis (GSEA) showed that cell cycle pathway was correlative with the TMEM48 expression. Additionally, real-time PCR and western blot analysis revealed that several cell cycle and DNA replication genes, including Cyclin B1, CDK1, CDC6, PCNA, and RCF4, were reduced after TMEM48 knockdown. Additionally, inhibition of TMEM48 in NSCLC cells significantly stimulated cell apoptosis, while notably repressed cell adhesion, migration, invasion, and tumorigenicity in nude mice. Our data provide insight into the biological relevance of TMEM48 in NSCLC progression and highlight its usefulness as a prognostic factor and potential therapeutic target in NSCLC.

Proteostasis is the process of regulating intracellular proteins to maintain the balance of the cell proteome, which is crucial for cancer cell survival. Several proteases located in the cytoplasm, mitochondria, lysosome, and extracellular environment have been identified as potential antitumor targets because of their involvement in proteostasis. Although the discovery of small-molecule inhibitors targeting proteases faces particular challenges, rapid advances in chemical biology and structural biology, and the new technology of drug discovery have facilitated the development of promising protease modulators. In this review, the protein structure and function of important tumor-related proteases and their inhibitors are presented. We also provide a prospective on advances and the outlook of new drug strategies that target these proteases.