Lung adenocarcinoma follows a stepwise progression from pre-invasive to invasive. However, there remains a knowledge gap regarding molecular events from pre-invasive to invasive. Here, we conduct a comprehensive proteogenomic analysis comprising whole-exon sequencing, RNA sequencing, and proteomic and phosphoproteomic profiling on 98 pre-invasive and 99 invasive lung adenocarcinomas. The deletion of chr4q12 contributes to the progression from pre-invasive to invasive adenocarcinoma by downregulating SPATA18, thus suppressing mitophagy and promoting cell invasion. Proteomics reveals diverse enriched pathways in normal lung tissues and pre-invasive and invasive adenocarcinoma. Proteomic analyses identify three proteomic subtypes, which represent different stages of tumor progression. We also illustrate the molecular characterization of four immune clusters, including endothelial cells, B cells, DCs, and immune depression subtype. In conclusion, this comprehensive proteogenomic study characterizes the molecular architecture and hallmarks from pre-invasive to invasive lung adenocarcinoma, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease.

It has been well established that tumor-infiltrating lymphocytes (TILs) play a critical role in the pathogenesis and progression of clear cell renal cell carcinoma (ccRCC). However, the mechanism on the interactions between TILs and tumor cells in the tumor-immune microenvironment remains unclear. In the present study, the expression of Response Gene to Complement 32 (RGC-32) was evaluated using immunohistochemistry. We analyzed the associations of RGC-32 expression with patient characteristics and survival. We also assessed TILs and their subsets (CD3+, CD4+, CD8+ and PD-1+) in the tumor nest. The level of RGC-32 expression was positively correlated with ISUP grade and Ki67 expression and was an independent poor prognosis factor of patients with ccRCC. RGC-32 expression was negatively correlated with the infiltration of TIL and CD3+T cells, but positively correlated with infiltration of PD-1+cells. In vitro studies showed that RGC-32 expression in renal cancer cells was downregulated by activated immune cells. Further investigation revealed that RGC-32 expression in renal cancer cells was inhibited by TNF-α and IL-1β secreted by activated immune cells. Collectively, these data indicate that RGC-32 could be a novel prognostic and druggable target related to the tumor-immune microenvironment in renal cancer.

Background: Radiation therapy plays an important role in the treatment of patients with non-small cell lung cancer (NSCLC). However, the radiocurability is greatly limited because of radioresistance which leads to treatment failure, tumor recurrence, and metastasis. Cancer stem cell (CSC) has been identified as the main factor that contributes to radiation resistance. SOX2, one of the transcription factors specifically expressed in CSC, is involved in tumorigenesis, progression, and maintenance of cell stemness. But the association between SOX2 and NSCLC radioresistance is not clear now. Methods: We constructed the radiotherapy-resistant cell line of NSCLC by multiple radiotherapy treatments. Colony formation assay, western blot, and immunofluorescence were performed to detect the radiosensitivity of cells. Western blot, qRT-PCR, and sphere formation assay were used to detect CSC characteristics of cells. Wound healing assay and Transwell assay were used to determine cell migration motility. The SOX2-upregulated model and SOX2-downregulated model was constructed by lentivirus transduction. Finally, the expression and clinical relevance of SOX2 in NSCLC were investigated by bioinformatics analysis based on TCGA and GEO datasets. Results: The expression of SOX2 was increased in radioresistant cells and a trend of dedifferentiation were observed. The results of wound healing assay and Transwell assay showed that SOX2 overexpression significantly promote the migration and invasion of NSCLC cells. Mechanistically, overexpression of SOX2 enhanced radioresistance and DNA damage repair capability of parental cells, while down-regulation of SOX2 led to decreased radioresistance and DNA repair ability in radioresistant cells, all of which were related to cells dedifferentiation regulated by SOX2. In addition, bioinformatics analysis show that high expression of SOX2 was strongly associated with the progression and poor prognosis of patients with NSCLC. Conclusions: Our study revealed that SOX2 regulates radiotherapy resistance in NSCLC via promoting cell dedifferentiation. Therefore, SOX2 may be a promising therapeutic target for overcoming radioresistance in NSCLC, providing a new perspective to improve the curative effect.

Radioresistance challenges the clinical outcomes of nasopharyngeal carcinoma (NPC). The 3‐phosphoinositide‐dependent protein kinase 1 (PDK1) is a crucial kinase of PI3K/AKT signaling pathway which has been implicated in the process of radioresistance. However, the role of PDK1 in NPC remains largely unclear.

BACKGROUND:Bladder cancer (BLCA) is one of the most common malignancies worldwide. One of the main reasons for the unsatisfactory management of BLCA is the complex molecular biological mechanism. Annexin A1 (ANXA1), a Ca2+-regulated phospholipid-binding protein, has been demonstrated to be implicated in the progression and prognosis of many cancers. However, the expression pattern, biological function and mechanism of ANXA1 in BLCA remain unclear. METHODS:The clinical relevance of ANXA1 in BLCA was investigated by bioinformatics analysis based on TCGA and GEO datasets. Immunohistochemical (IHC) analysis was performed to detect the expression of ANXA1 in BLCA tissues, and the relationships between ANXA1 and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to study the biological functions of ANXA1 in BLCA. Finally, the potential mechanism of ANXA1 in BLCA was explored by bioinformatics analysis and verified by in vitro and in vivo experiments. RESULTS:Bioinformatics and IHC analyses indicated that a high expression level of ANXA1 was strongly associated with the progression and poor prognosis of patients with BLCA. Functional studies demonstrated that ANXA1 silencing inhibited the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of BLCA cells in vitro, and suppressed the growth of xenografted bladder tumors in vivo. Mechanistically, loss of ANXA1 decreased the expression and phosphorylation level of EGFR and the activation of downstream signaling pathways. In addition, knockdown of ANXA1 accelerated ubiquitination and degradation of P-EGFR to downregulate the activation of EGFR signaling. CONCLUSIONS:These findings indicate that ANXA1 is a reliable clinical predictor for the prognosis of BLCA and promotes proliferation and migration by activating EGFR signaling in BLCA. Therefore, ANXA1 may be a promising biomarker for the prognosis of patients with BLCA, thus shedding light on precise and personalized therapy for BLCA in the future.

Egl-9 Family Hypoxia Inducible Factor 1 (EGLN1) is a proline hydroxylase mediating degradation of hypoxia-inducible factor α (HIFα) through the ubiquitination system. Studies have indicated an essential role for EGLN1 in angiogenesis and tumorigenesis. However, there is no consensus on the regulation of EGLN1 and its mechanism of action on nasopharyngeal carcinoma (NPC). This study explored the association of the expression of EGLN1 with characteristics of NPC tumors and its underlying mechanism. We found that the expression of EGLN1 showed a positive correlation with tumor T classification and clinical staging of patients with NPC. EGLN1 could promote cell proliferation, invasion and migration, and even enhance the cancer stem cells (CSCs) prosperity and radioresistance of NPC cells. Mechanistically, EGLN1 facilitated degradation of tumor protein p53 through the ubiquitination system. This effect could be weakened in the presence of dimethyloxalylglycine (DMOG), suggesting that EGLN1 down-regulated p53 based on its hydroxylase activity. In conclusion, overexpression of EGLN1 promoted oncogenesis and induced a CSC-like phenotype in NPC cells, then enhancing the ability for radioresistance by interacting with p53 in a hydroxylase-dependent manner. Thus, EGLN1 might serve as a potential therapeutic target for NPC.

Background Fermitin family member 1 (FERMT1) is significantly overexpressed in human cancers and associated with poor prognosis, but its contributions to tumorigenesis and nasopharyngeal carcinoma (NPC) progression remain unclear. Methods The public GEO database was examined to investigate the role of FERMT1. Immunohistochemistry (IHC) staining of FERMT1 was performed in NPC tissues to corroborate the results. Western blotting and qRT-PCR were performed to test the expression of related proteins and mRNAs. Cell counting kit-8 assay (CCK8 assay) and colony formation assays were carried out to investigate the association of FERMT1 expression with NPC cell proliferation. The wound healing assay and Transwell assay were used to detect the migration and invasion of NPC cells. Flow cytometric analysis was conducted to detect the cell cycle transition of NPC cells. Co-immunoprecipitation (Co-IP) was employed to identify the correlation of FEMRT1 and Nod-like receptor family protein 3 (NLRP3). Xenograft tumors were generated to investigate the effect of FERMT1 on the growth of NPC cells in vivo. Results Here, we found that FERMT1 was upregulated in NPC tissues and correlated with the clinicopathological characteristics of NPC patients. Moreover, knockdown of FERMT1 significantly decreased cell proliferation, migration and invasion by mediating epithelial-mesenchymal transition (EMT) and cell cycle arrest of NPC cells both in vitro and in vivo. Knockdown FERMT1 inhibited EMT through directly binding to the NLRP3 and inhibited NF-kB signaling pathway. Conclusion These data indicated that FERMT1 could be a good potential therapeutic target for NPC treatment.

目的 观察培美曲塞+奈达铂联合贝伐珠单抗治疗后培美曲塞联合贝伐珠单抗维持治疗方案在晚期非鳞非小细胞肺癌患者中的疗效和安全性,并探讨影响该化疗方案疗效的相关因素.方法 收集2015年6月—2018年6月经病理确诊的50例晚期非鳞非小细胞肺癌患者,所有患者均接受培美曲塞+奈达铂联合贝伐珠单抗治疗,并对治疗后疾病未进展的患者给予培美曲塞联合贝伐珠单抗维持治疗,直至疾病进展或出现不可耐受的不良反应.对患者的近期疗效和不良反应进行分析.结果 50例患者的客观缓解率(ORR)和疾病控制率(DCR)分别为42％(21/50)和86％(43/50),中位无进展生存期(PFS)为11个月(95％CI:8.1～13.9).治疗相关不良反应主要为骨髓抑制,但均可耐受,无不良反应相关性死亡.结论 培美曲塞+奈达铂联合贝伐珠单抗治疗后培美曲塞联合贝伐珠单抗维持化疗方案在晚期非鳞非小细胞肺癌患者中有较好的疗效和安全性.

AbstractBackgroundCancer patients are at a high risk of being infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), and are more likely to develop severe illness and have higher mortality once infected. In the COVID‐19 pandemic, it is urgent to understand the effects of antitumor therapy on the prognosis of patients with COVID‐19.MethodsA systematic literature search was conducted in PubMed, Cochrane Library, Embase, MedRxiv, and Chinese National Knowledge Infrastructure (CNKI) until 21 June 2020. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were evaluated using a random effects model to analyze the effects of antitumor therapies on COVID‐19 patients.ResultsFor cancer patients with COVID‐19, the death events related to antitumor treatment were higher than those with no antitumor treatment (OR = 1.55; 95% CI 1.07–2.25; p = 0.021). Compared with patients in the survival group, the non‐survival group showed no significant differences in patients who received antitumor therapy. Compared with patients in the non‐severe group, the severe group was more likely to receive antitumor therapy (OR = 1.50; 95% CI 1.02–2.19; p = 0.037) and there was a significant difference. The incidence of severe events was higher in the subgroup of chemotherapy (OR = 1.73; 95% CI 1.09–2.73).ConclusionThe synthesized evidence suggests that cancer patients with COVID‐19 who received antitumor treatment shortly before symptom onset are more likely to experience severe symptoms and have high mortality. Receiving chemotherapy is an unfavorable factor for the prognosis of cancer patients with COVID‐19.

Based on the ESTIMATE algorithm, we acquired the immune/stromal scores of cervical squamous cell carcinoma (CSCC) patients collected from The Cancer Genome Atlas (TCGA) dataset. Subsequently, we analyzed the DEGs between high- and low immune score groups using R package edgeR and performed K-M analysis to illustrate the relationship between differentially expressed genes (DEGs) and the overall survival to select survival-related DEGs. Then the LASSO regression model was constructed with the package “glmnet” in R to evaluate the riskscore of each patient. Finally, we developed a nomogram composing riskscore and clinicopathological characteristics to predict the overall survival (OS) of CSCC patients. The R software v3.6.1 was used for statistical analyses. All statistical tests were two-tailed.

Background: Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high mortality and morbidity worldwide, but the underlying biological mechanisms of molecules and tumor infiltrating-immune cells (TIICs) are still unknown. Methods and Results: We obtained mRNAs, lncRNAs, and miRNAs expression profiles of 546 HNSCC from The Cancer Genome Atlas (TCGA) database to develop a ceRNA network. CIBERSORT was employed to estimate the fraction of 22 types of TIICs in HNSCC. Univariate and multivariate Cox regression and lasso regression analyses were used to develop prognostic signatures. Then, two novel risk signatures were constructed respectively based on six ceRNAs (ANLN, KIT, PRKAA2, NFIA, PTX3 and has-miR-148a-3p) and three immune cells (naïve B cells, regulatory T cells and Neutrophils). Kaplan-Meier (K-M) analysis and Cox regression analysis further proved that these two signatures were significant prognostic factors independent of multiple clinicopathological characteristics. Two nomograms were built based on ceRNAs-riskScore and TIICs-riskScore that could be used to predict the prognosis of HNSCC. Co-expression analysis showed significant correlations between miR-148a-3p and naive B cells, naive B cells and plasmas cells. Conclusion: Through construction of the ceRNA network and estimation of TIICs, we established two risk signatures and their nomograms with excellent utility, which indicated the potential molecular and cellular mechanisms, and predicted the prognosis of HNSCC.

Lung adenocarcinoma (LUAD) is a major pathological type of lung cancer. Understanding the mechanism of LUAD at the molecular level is important for a clinical decision. In this study, we use bioinformatic analysis to explore the prognostic value of P4HA1 in lung adenocarcinoma (LUAD) and the relationship with prognosis and tumor-infiltrating immune cells (TIICs). The results showed that the expression of P4HA1 was significantly higher in tumor tissues than in normal tissues for LUAD patients. Upregulated P4HA1 was related to stage and T classification. Kaplan-Meier analysis indicated that upregulation of P4HA1 was significantly related to worse overall survival (OS). Univariate and multivariate Cox analysis indicated P4HA1 remained to be an independent prognostic factor. GSEA showed that several cancer-related and immune-related signaling pathways exhibited prominently differential enrichment in P4HA1-high expression phenotype. In addition, the expression of P4HA1 was significantly correlated with proportion of several TIICs, particularly B cells and CD4+ T cells. In conclusion, our study confirmed that P4HA1 is a promising biomarker of poor prognosis and relates to immune infiltrates in LUAD.

OBJECTIVES:Use of immune checkpoint inhibitors as first-line treatment for advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) remains controversial. Clinical trials comparing single-drug immunotherapy (IO) with immunotherapy plus chemotherapy (IC) are lacking. We aimed to compare the efficacy of IO alone with that of IC as first-line treatment for advanced NSCLC.DESIGN:Systematic review.DATA SOURCES:PubMed, the Cochrane Library and Embase for related studies on NSCLC; ClinicalTrials.gov, American Society of Clinical Oncology Meeting Library and World Conference on Lung Cancer for relevant conference abstracts (to July 2019).ELIGIBILITY CRITERIA:Articles meeting the following criteria were selected: (1) randomised controlled trials on NSCLC treatment, (2) all individuals in the studies had not received treatment previously and (3) research on IO monotherapy using programmed death-1/programmed death ligand-1 (PD-L1) inhibitors or IC.DATA EXTRACTION AND SYNTHESIS:After reading the original literature, two reviewers independently extracted the relevant information. The primary outcomes were progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). We also extracted data on treatment-related adverse events and immune-related adverse events (irAEs).RESULTS:Overall, 10 randomised controlled clinical trials (n=5765) were included. As first-line treatment for advanced NSCLC, IC tended to yield better PFS, OS and ORR than did IO. Furthermore, IC yielded significantly better PFS than IO when tumour PD-L1 expression was at least 50% (HR: 1.81, 95% CI: 1.18 to 2.78) and yielded a better OS and PFS when tumour PD-L1 expression was at least 1%; IO resulted in fewer adverse events than did IC. However, the incidence of irAEs was higher for IO than for IC.CONCLUSIONS:The findings of the indirect comparison indicate that IC as first-line treatment for advanced NSCLC is significantly more effective than IO in patients with PD-L1 expression in at least 50% of tumour cells.TRIAL REGISTRATION NUMBER:CRD 42018116589.

In recent years, more and more studies have shown that the expression of miRNAs is closely related to the occurrence of tumors and plays an irreplaceable role in the development and metastasis of tumors. The research was focused on lung squamous cell carcinoma. The data information is downloaded from the TCGA database and analyzed for variance, which is then verified in the GEO database. Then differential expression of miRNAs was found and survival analysis was performed, through the cut – off standard(P<0.05,|logFC|≥2), we screen the 38 up-regulated miRNAs and 14 down-regulated miRNAs from the TCGA. Finally, after the verification on the GEO database, four up-regulated miRNAs (hsa-mir-205, hsa-mir-210, hsa-mir-182, hsa-mir-224) and one down-regulated miRNA (hsa-mir-451) were obtained, which provide a new direction for the diagnosis of lung squamous cell carcinoma. In the survival analysis, it was found that the expression state of hsamir-210 was significantly correlated with patient survival. The results in the univariate and multivariate Cox analysis indicated that hsa-mir-210 was an independent prognostic factor on lung squamous cell carcinoma. The functional enrichment analysis showed that hsa-mir-210 was closely related to positive and negative regulation of cell proliferation, DNA transcription, VEGF signaling pathway, MAPK signaling pathway, hif-1 signaling pathway and choline metabolic pathway. In summary, this study suggested that hsa-mir-210 could be a potential prognostic factor for lung squamous cell carcinoma. Author Summary MicroRNAs are single-stranded small molecular RNA that participate in the regulation of various biological functions through indirect regulation of gene expression, and have been reported to play an important role in the occurrence, development, invasion and metastasis of tumors. In recent years, the research on miRNAs has become increasingly hot, and the role of miRNAs in tumor has been proved more and more. The subjects of this study were squamous cell carcinoma in lung cancer with relatively few studies on miRNAs. Through high-throughput data analysis, miRNAs with differential expression between lung squamous cell carcinoma tissues and normal tissues were found. These differentially expressed miRNAs provide a new direction for the early diagnosis of patients. Then, survival analysis was conducted to find the miRNAs significantly correlated with the total survival time of patients, and multi-factor analysis was conducted to exclude the influence of other clinical factors, and independent risk factors (miRNAs) affecting the survival of patients were determined, so as to provide new targets for the treatment and survival prediction of patients.

BackgroundCirculating tumor DNA (ctDNA) harboring tumor-specific genetic and epigenetic aberrations allows for early detection and real-time monitoring of tumor dynamics. In this study, we aimed to evaluate the potential of parallel serial assessment of somatic mutation and methylation profile in monitoring the response to osimertinib of epidermal growth factor receptor (EGFR) T790M-positive advanced lung adenocarcinoma patients.MethodsParallel somatic mutation and DNA methylation profiling was performed on a total of 85 longitudinal plasma samples obtained from 8 stage IV osimertinib-treated EGFR T790M-positive lung adenocarcinoma patients.ResultsOur results revealed a significant correlation between the by-patient methylation level with the maximum allele fraction (maxAF, P=0.0002). The methylation levels were significantly higher in the plasma samples of patients with detectable somatic mutations than patients without somatic mutations (P=0.0003) and healthy controls (P=0.0018). Moreover, analysis of both the DNA methylation level and maxAF revealed four trends of treatment response. Collectively, the decrease in methylation level and maxAF reflected treatment efficacy, while the gradual increase reflected impending disease progression (PD). Elevated methylation levels and maxAF were observed in 6 and 5 patients in an average lead-time of 3.0 and 1.9 months, respectively, prior to evaluation of PD using radiological imaging.ConclusionsDNA methylation profiling has the potential to predict disease relapse prior to evaluation through radiological modalities, suggesting that serial assessment of methylation level in combination with somatic mutation profiling are reliable methods for treatment monitoring. These methods should thus be incorporated with imaging modalities for a more comprehensive work-up of treatment response, particularly for patients treated with targeted therapies.