Roles of Cellular Neighborhoods in Lung Cancer.

High-risk human papillomavirus (HPV)16/18 infection in the development of lung cancer has previously been identified, and fragile histidine triad (FHIT) loss and p53 mutation are frequently observed in the disease. However, the association between these factors has not been well studied. The present study aimed to further investigate the significance of HPV infection, FHIT loss and p53 mutations in the development of lung cancer and their possible associations. DNA was extracted from paraffin-embedded specimens from 88 cases of squamous cell carcinoma (SCC), 56 of adenocarcinoma (AC), 36 of small cell lung carcinoma (SCLC) and 110 non-cancer control cases of lung neoplasms. The prevalence of HPV infection was determined by polymerase chain reaction analysis, and FHIT loss and p53 mutations were detected by immunohistochemistry. The χ2, Fisher's exact and Pearson correlation tests were applied for statistical analysis. The results of the present study demonstrated that HPVL1 (the major capsid protein of HPV), HPV16 and HPV18 infection were more prevalent in the lung cancer samples compared with the non-cancer controls (all P<0.001). FHIT loss occurred more frequently in the lung cancer samples (44.44%) compared with the non-cancer controls (7.25%) (P<0.001). FHIT loss in the HPVL1-positive group was significantly increased compared with the HPVL1-negative group in the lung cancer cases and the non-cancer controls (P<0.05). In the lung cancer cases, the p53 mutation rates in the HPVL1- and HPV16/18-positive groups were significantly increased compared with the HPVL1- and HPV16/18-negative groups (P<0.05). In the 180 lung cancer cases, the coexistence rate of FHIT loss and a history of smoking was 38.33% (69/180; Pearson contingency coefficient of r=0.318; P<0.001). FHIT loss and p53 mutation exhibited a synergistic effect on HPV-associated lung cancer (Pearson contingency coefficient r=0.357, P<0.001). The present study demonstrated that FHIT loss may be important in the occurrence of lung cancer, particularly in lung SCCs. FHIT loss may therefore be used as an early indicator for lung cancer, particularly for patients with a history of smoking. HPV infection in lung tumorigenesis may, at least in part, be mediated through FHIT loss. FHIT loss and p53 mutation may coordinate together in the development of HPV-associated lung cancer, and accelerate the occurrence and development of lung cancer.

Lung cancer is one of the 10 most common cancers in the world, which seriously affects the normal life and health of patients. According to the investigation report, the 3-year survival rate of patients with lung cancer is less than 20%. Heredity, the environment, and long-term smoking or secondhand smoke greatly promote the development and progress of the disease. The mechanisms of action of the occurrence and development of lung cancer have not been fully clarified. As a new type of gas signal molecule, hydrogen sulfide (H2S) has received great attention for its physiological and pathological roles in mammalian cells. It has been found that H2S is widely involved in the regulation of the respiratory system and digestive system, and plays an important role in the occurrence and development of lung cancer. H2S has the characteristics of dissolving in water and passing through the cell membrane, and is widely expressed in body tissues, which determines the possibility of its participation in the occurrence of lung cancer. Both endogenous and exogenous H2S may be involved in the inhibition of lung cancer cells by regulating mitochondrial energy metabolism, mitochondrial DNA integrity, and phosphoinositide 3-kinase/protein kinase B co-pathway hypoxia-inducible factor-1α (HIF-1α). This article reviews and discusses the molecular mechanism of H2S in the development of lung cancer, and provides novel insights for the prevention and targeted therapy of lung cancer.

Lung cancer is the most common and fatal malignant tumor in the world. The tumor microenvironment (TME) is closely related to the occurrence and development of lung cancer, in which the inflammatory microenvironment plays an important role. Inflammatory cells and inflammatory factors in the tumor inflammatory microenvironment promote the activation of the NF-κB and STAT3 inflammatory pathways and the occurrence, development, and metastasis of lung cancer by promoting immune escape, tumor angiogenesis, epithelial–mesenchymal transition, apoptosis, and other mechanisms. Clinical and epidemiological studies have also shown a strong relationship among chronic infection, inflammation, inflammatory microenvironment, and lung cancer. The relationship between inflammation and lung cancer can be better understood through the gradual understanding of the tumor inflammatory microenvironment, which is advantageous to find more therapeutic targets for lung cancer.

BackgroundLung cancer is one of the most malignant tumors. However, neither the pathogenesis of lung cancer nor the prognosis markers are completely clear. The purpose of this study is to screen the diagnostic or prognostic markers of lung cancer.MethodsTCGA and GEO datasets were used to analyze the relationship between lung cancer-related genes and lung cancer samples. Common differential genes were screened, and a univariate Cox regression analysis was used to screen survival related genes. A univariable Cox proportional hazards regression analysis was used to verify the genes and construct risk model. The key factors affecting the prognosis of lung cancer were determined by univariate and multivariate regression analyses. The ROC curve, AUC and the survival of each risk gene was analyzed. Finally, the biological functions of high- and low-risk patients were explored by GSEA and an immune-infiltration analysis.ResultsBased on the common differential genes, 13 genes significantly related to lung cancer survival were identified. Eight risk genes (CBFA2T3, DENR, EGLN1, FUT2, FUT4, PCDH7, PHF14, and STX3) were screened out. The results showed that risk status may be an independent prognostic factor, and the risk score predicted the prognosis of lung cancer. CBFA2T3 and STX3 are protective genes, while DENR, EGLN1, FUT4 and PCDH7 are dangerous genes. These 6 genes can be used as independent lung cancer prognosis markers. The corresponding biological functions of genes expressed in high-risk patients were mostly related to tumor proliferation and inflammatory infiltration. Neutrophil, CD8+T, Macrophage M0, Macrophage M1- and mDC-activated cells were high in high-risk status samples.ConclusionsCBFA2T3, STX3, DENR, EGLN1, FUT4, and PCDH7 are important participants in the occurrence and development of lung cancer. High-risk patients display serious inflammatory infiltration. This study not only provides insight into the mechanism of occurrence and development of lung cancer, but also provides potential targets for targeted therapy of lung cancer.

The present study aimed to investigate the correlation of the of hemoglobin A1c (HbA1c), C-peptide and insulin-like growth factor-1 (IGF-1) levels with the development and progression of lung cancer. The serum HbA1c, C-peptide and IGF-1 levels were measured and compared between 80 lung cancer patients and 80 healthy controls; furthermore, their correlation with histopathological type and tumor stage was analyzed in the 80 lung cancer patients. Our results suggested that the levels of HbA1c, C-peptide and IGF-1 were significantly increased in patients with lung cancer compared to those in the control group (P<0.05). In addition, the levels of C-peptide and IGF-1 were significantly higher in the small-cell lung cancer group (n=18), the stage III-IV (n=55) group and the lung cancer with diabetes mellitus group (n=43) compared to those in the non-small-cell lung cancer group (n=62), the stage I-II lung cancer group (n=25) and the lung cancer without diabetes group (n=37), respectively (P<0.05). Thus, the present study suggests that the increased serum HbA1c, C-peptide and IGF-1 levels are significantly correlated with the development and progression of lung cancer.

Lung cancer is a major threat to human health. The molecular mechanisms related to the occurrence and development of lung cancer are complex and poorly known. Exploring molecular markers related to the development of lung cancer is helpful to improve the effect of early diagnosis and treatment. Long non-coding RNA (lncRNA) THAP7-AS1 is known to be highly expressed in gastric cancer, but has been less studied in other cancers. The aim of the study is to explore the role and mechanism of methyltransferase-like 3 (METTL3) mediated up-regulation of N6-methyladenosine (m6A) modified lncRNA THAP7-AS1 expression in promoting the development of lung cancer. Samples of 120 lung cancer and corresponding paracancerous tissues were collected. LncRNA microarrays were used to analyze differentially expressed lncRNAs. THAP7-AS1 levels were detected in lung cancer, adjacent normal tissues and lung cancer cell lines by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The diagnostic value of THAP7-AS1 in lung cancer and the relationship between THAP7-AS1 expression and survival rate and clinicopathological parameters were analyzed. Bioinformatics analysis, methylated RNA immunoprecipitation (meRIP), RNA pull-down and RNA-immunoprecipitation (RIP) assay were used to investigate the molecular regulation mechanism of THAP7-AS1. Cell proliferation, migration, invasion and tumorigenesis of SPC-A-1 and NCI-H1299 cells were determined by MTS, colony-formation, scratch, Transwell and xenotransplantation in vivo, respectively. Expression levels of phosphoinositide 3-kinase/protein kenase B (PI3K/AKT) signal pathway related protein were detected by Western blot. Expression levels of THAP7-AS1 were higher in lung cancer tissues and cell lines (P<0.05). THAP7-AS1 has certain diagnostic value in lung cancer [area under the curve (AUC)=0.737], and its expression associated with overall survival rate, tumor size, tumor-node-metastasis (TNM) stage and lymph node metastasis (P<0.05). METTL3-mediated m6A modification enhanced THAP7-AS1 expression. The cell proliferation, migration, invasion and the volume and mass of transplanted tumor were all higher in the THAP7-AS1 group compared with the NC group and sh-NC group of SPC-A-1 and NCI-H1299 cells, while the cell proliferation, migration and invasion were lower in the sh-THAP7-AS1 group (P<0.05). THAP7-AS1 binds specifically to Cullin 4B (CUL4B). The cell proliferation, migration, invasion, and expression levels of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphoinositide-3 kinase, catalytic subunit delta (PIK3CD), phospho-phosphatidylinositol 3-kinase (p-PI3K), phospho-protein kinase B (p-AKT) and phospho-mammalian target of rapamycin (p-mTOR) were higher in the THAP7-AS1 group compared with the Vector group of SPC-A-1 and NCI-H1299 cells (P<0.05). LncRNA THAP7-AS1 is stably expressed through m6A modification mediated by METTL3, and combines with CUL4B to activate PI3K/AKT signal pathway, which promotes the occurrence and development of lung cancer.

BackgroundLung cancer is the leading cause of cancer-related deaths worldwide (Ferlay et al., Int J Cancer 136:E359–386, 2015). In addition, lung cancer is associated with the highest mortality among all cancer types (Wu et al., Exp Ther Med 16:3004–3010, 2018). Previous studies report that microbiota play an important role in lung cancer. Notably, changes in lung and gut microbiota, are associated with progression of lung cancer. Several studies report that lung and gut microbiome promote lung cancer initiation and development by modulating metabolic pathways, inhibiting the function of immune cells, and producing pro-inflammatory factors. In addition, some factors such as microbiota dysbiosis, affect production of bacteriotoxins, genotoxicity and virulence effect, therefore, they play a key role in cancer progression. These findings imply that lung and gut microbiome are potential markers and targets for lung cancer. However, the role of microbiota in development and progression of lung cancer has not been fully explored.PurposeThe aim of this study was to systemically review recent research findings on relationship of lung and gut microbiota with lung cancer. In addition, we explored gut–lung axis and potential mechanisms of lung and gut microbiota in modulating lung cancer progression.ConclusionPulmonary and intestinal flora influence the occurrence, development, treatment and prognosis of lung cancer, and will provide novel strategies for prevention, diagnosis, and treatment of lung cancer.

P34 Identification of the Genetic Determinants of Susceptibility to Lung Cancer in a Moroccan Cohort

肺癌为全球性高发病率、高死亡率疾病，严重影响人类健康。其中肺部慢性炎症的长期存在与肺癌的发生发展关系密切，中性粒细胞不但参与急、慢性炎症反应，而且参与肿瘤微环境（tumor-microenvironment, TME）中的组成，与肿瘤的发生、发展密切相关。近年来研究发现，肿瘤相关中性粒细胞（tumor-associated neutrophils, TANs）在肺癌的发生和发展中发挥着重要的作用。本文就肿瘤相关中性粒细胞在肺癌中的作用、机制以及临床意义进行综述。

PurposeLung cancer represents one of the most frequent solid tumors. Adenocarcinoma is a common type of tumor and a significant threat to individual health globally. MicroRNAs (miRNAs) are recognized as critical governors of gene expression during carcinogenesis, while their effects on lung cancer occurrence and development are required for further investigation. Herein, the functional role of miR-210-3p and its regulation mechanism were characterized in lung cancer.MethodsA total of 50 pairs of tumor and tumor-free lung tissues were surgically resected from lung cancer patients. Dual-luciferase reporter assay and RNA immunoprecipitation assay were performed to examine USF1 binding with miR-210-3p and PCGF3. Cultured human lung cancer cells A549 were assayed for viability, apoptosis, migration, and invasion in vitro by CCK-8 test, flow cytometry, transwell chamber assays, tumorigenesis, and lymph node metastasis in vivo by mouse xenograft experiments.ResultsmiR-210-3p was upregulated in lung cancer tissues. The inhibition of miR-210-3p by specific inhibitor tempered lung cancer development and metastasis in vitro and in vivo. miR-210-3p targeted USF1 and inhibited its expression. USF1 was bound with PCGF3, which increased its transcription. PCGF3-specific knockdown mimicked the effect of miR-210-3p on lung cancer development and metastasis in vitro and in vivo.ConclusionThe current study demonstrated that miR-210-3p facilitates lung cancer development and metastasis by impairing USF1-mediated promotion of PCGF3, which provides a better understanding of the mechanism of lung cancer development and metastasis.

Lung cancer, one of the most malignant tumors, has extremely high morbidity and mortality, posing a serious threat to global health. It is an urgent need to fully understand the pathogenesis of lung cancer and provide new ideas for its treatment. Interestingly, accumulating evidence has identified that transfer RNAs (tRNAs) and tRNA metabolism–associated enzymes not only participate in the protein translation but also play an important role in the occurrence and development of lung cancer. In this review, we summarize the different aspects of tRNA metabolism in lung cancer, such as tRNA transcription and mutation, tRNA molecules and derivatives, tRNA-modifying enzymes, and aminoacyl-tRNA synthetases (ARSs), aiming at a better understanding of the pathogenesis of lung cancer and providing new therapeutic strategies for it.

Cumulative evidence from both in vitro and animal studies suggests that cyclooxygenase-2 (COX-2) may be involved in the development and progression of lung cancer. Overproduction of prostaglandin E synthase and prostaglandin E2 (PGE2), one of the end products of the COX-2 pathway, has been implicated in the pathogenesis of non-small cell lung cancer. On the other hand, evidence suggests that prostacyclin (PGI2), another end products of the COX-2 pathway, may differ from other bioactive prostaglandins and may exert cancer-inhibitory effects on the development of lung cancer. PGE2 is quickly converted to 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), a major PGE2 metabolite and excreted in urine. PGI2 is rapidly converted into 6-keto-PGF1a, a chemically stable but biologically inactive hydration product. Circulatory 6-keto-PGF1a undergoes ß-oxidation and appears in the urine as 2,3-dinor-6-keto-PGF1a (PGI-M), the primary breakdown product of PGI2. Urinary PGE-M and PGI-M are stable compounds and can be measured accurately and reliably with newly developed and validated LC-MS and GC-MS assays. In this study, we evaluated the association of pre-diagnostic urinary PGE-M and PGI-M levels with subsequent risk of developing lung cancer. We conducted a nested case-control study using resources of the Shanghai Men's Health Study, a prospective cohort study, in which 61,491 Chinese men aged 40-74 years were recruited from 2002 to 2006 and followed for up to 7 years. Urinary PGE-M and PGI-M in 349 incident lung cancer patients were compared to 349 matched controls. Overall, the geometric mean of baseline level of urinary PGE-M did not differ significantly between cases and controls. Compared with the lowest quartile, the risks (odds ratios, ORs) of developing lung cancer were non-significantly elevated (1.48, 95% CI=0.91-2.40 for the highest quartile). No dose-response relationship was evident. The baseline level of urinary PGI-M was more than 20% higher in cases than in controls. The ORs for developing lung cancer increased from 1.0 to 1.14 (95% CI=0.66-1.95), 1.45 (95% CI=0.86-2.45), and 1.70 (95% CI=0.99-2.92) across the quartiles of urinary PGI-M levels (P for trend=0.0056). Excluding 63 case-control pairs who were diagnosed with lung cancer within one year of follow-up did not change the associations for PGE-M and PGI-M. No interaction was found between PGE-M and PGI-M in relation to lung cancer risk. In summary, using data from a large prospective cohort study, we found that high levels of urinary PGI-M, and possibly PGE-M, were associated with subsequent risk of developing lung cancer. Our data suggest that high activity of the COX-2 pathway, rather than the prostaglandin E2 alone, may play a major role in lung cancer development. Further studies are needed to evaluate these two urinary markers as possible biomarkers for lung cancer risk assessment. Citation Format: Qiuyin Cai, Yong-Bing Xiang, Wanqing Wen, Ginger L. Milne, Hong-Lan Li, Jie Wu, Gong Yang, Jing Gao, Tsogzolmaa Dorjgochoo, Yu-Tang Gao, Wei Zheng, Xiao Ou Shu. Prospective study of urinary prostaglandin E2 and prostacyclin metabolites and lung cancer risk . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 122. doi:10.1158/1538-7445.AM2013-122

The pathogenesis mechanism of lung cancer is very complex, with high incidence and mortality. Serpin family A member 3 (SERPINA3) expression levels were reduced in the sera of patients with lung cancer and may be a candidate diagnostic and prognostic survival biomarker in lung cancer, as previously reported. However, the detailed biological functions of SERPINA3 in the pathogenesis of lung cancer remain unknown. In the present study, it was aimed to explore the effects of SERPINA3 on the occurrence of lung cancer. SERPINA3 expression was assessed using bioinformatics database analysis and experimental detection. Then, the biological effects of SERPINA3 were investigated in a cell culture system and a xenograft model of human lung cancer. The potential regulatory mechanism of SERPINA3 in lung cancer was explored by data‑independent acquisition mass spectrometry (DIA‑MS) detection and further validated by western blotting (WB). The results indicated that SERPINA3 expression levels were significantly downregulated in lung cancer tissues and cell lines. At the cellular level, it was revealed that overexpressed SERPINA3 inhibited cell growth, proliferation, migration and invasion and promoted the apoptosis of lung cancer cells. Moreover, overexpressed SERPINA3 enhanced the sensitivity of lung cancer cells to osimertinib. Invivo, a xenograft model of human lung cancer was established with BALB/c nude mice. After the injection of A549 cells, the tumor growth of the tumor‑bearing mice in the SERPINA3‑overexpressing group increased more slowly, and the tumor volume was smaller than that in the empty‑vector group. Mechanistically, a total of 65 differentially expressed proteins were identified. It was found that the speckle‑type POZ protein (SPOP) was significantly upregulated in SERPINA3‑overexpressing H157 cells using DIA‑MS detection and analysis. WB validation showed that SPOP expression increased, and NF‑kappaB (NF‑κB) p65 was inhibited in cell lines and tumor tissues of mice when SERPINA3 was overexpressed. The present findings suggest that SERPINA3 is involved in the development of lung cancer and has an antineoplastic role in lung cancer.

Recent study showed that inflammation was related to lung cancer. However, the exact cause of lung inflammation leading to carcinogenesis is unknown. MicroRNAs (miRNAs) are a group of endogenous non-coding small RNAs that regulate the activity of targeted mRNAs by inflammatory response in many diseases. MiR-451 was reported to relate to the development of lung cancer and metastasis of glioma. But the effect of miR-451 on cell proliferation, migration, and invasion of lung cancer is not really clear. In order to explore the molecular mechanism of the occurrence and development of lung cancer, we investigated the effect of human miR-451 on the proliferation, invasion, and metastasis in lung cancer cell line A549. The miR-451 expression construct was generated into pGenesil-1.1 and transfected into A549 cells. Results showed that the recombinant vectors were verified by sequencing. And miR-451 was over-expressed in A549 by real-time RT PCR. Furthermore, the proliferation, invasion, and metastasis of the cells in miR-451 group were inhibited significantly compared with those in control and A549 groups by MTT assay, Transwell invasion assay, and wound-healing assay. And the lung cancer metastasis factors (MMP-2, MMP-9, VEGF, and CXCR4) were decreased in miR-451 group by Western blot. Moreover, it was proved that inflammation-related gene-PSMB8 was a target for miR-451 by bioinformatics analysis and dual-luciferase reporter assay. And the protein expressions of PSMB8 and NOS2 were decreased in miR-451 group compared with those in control and A549 groups. Therefore, our findings indicated that miR-451 related to PSMB8/NOS2 inflammatory factors may suppress the development and migration of lung cancer, providing evidence for the role of miR-451 in lung cancer.

Background and ObjectiveLung cancer is one of the most common malignant tumors in the world, with a high incidence and a poor prognosis. The current treatment methods are limited, and novel treatment strategies are needed. Macrophages, as innate immune cells, interact with lung cancer cells in the tumor microenvironment and can influence the occurrence and development of lung cancer. This paper reviews the role of macrophages in lung cancer in relation to polarization, exosomes, cytokines, cell pathways and genes, and clinical prognosis.MethodsA structured literature search of PubMed, Web of Science Core Collection, and Embase was conducted from database inception to February 6, 2026. This was supplemented by cross-checking in Google Scholar and manual screening of reference lists from key reviews and landmark studies. Two authors independently screened titles and abstracts, and full texts were assessed according to designated inclusion criteria.Key Content and FindingsA comprehensively review of the multifaceted roles of macrophages in lung cancer development, progression, and therapeutic response was conducted. The origin and phenotypic polarization of macrophages were examined, with the functional heterogeneity between antitumor M1 macrophages and protumor M2 tumor-associated macrophages (TAMs) within the tumor microenvironment emerging as a prominent topic. Another important theme was the crosstalk between macrophages and lung cancer cells mediated by exosomes, inflammatory cytokines, and key signaling pathways, including NF-κB, STAT3/STAT6, and PI3K/AKT, as well as gene regulatory mechanisms. These interactions collectively promote tumor growth, angiogenesis, metastasis, immune suppression, and therapy resistance. Furthermore, the clinical and prognostic significance of macrophage infiltration patterns and polarization status in patients with lung cancer was examined. Overall, the targeting of macrophage polarization and macrophage-related signaling networks emerged as a promising strategy for improving lung cancer diagnosis, prognosis assessment, and immunotherapeutic outcomes.ConclusionsMacrophages act as central regulators of lung cancer progression and therapeutic response through their remarkable plasticity within the tumor microenvironment. The balance between antitumor M1 and protumor M2 macrophages, shaped by exosomes, cytokines, signaling pathways, and gene regulation, critically influences tumor growth, metastasis, immune evasion, and prognosis. Targeting macrophage polarization and macrophage-related pathways represents a promising strategy for improving the diagnosis of patients with lung through achieving more accurate prognostic evaluation and greater treatment efficacy.