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Lung adenocarcinoma (LUAD), responsible for nearly half of lung cancer cases, is one of the most prevalent and lethal malignant tumors globally. There is increasing evidence suggesting that the oncoprotein PLK1 plays a role in the onset and advancement of different types of cancer, including LUAD. Nonetheless, the precise mechanism by which PLK1 promotes tumorigenesis remains unclear. In this study, we demonstrate the upregulation of PLK1 in LUAD samples, which leads to a poor prognosis for LUAD patients. Intriguingly, PLK1 enables to bind to LZTS2 and promote its phosphorylation without affecting LZTS2 degradation. Furthermore, we identify that Ser451 is a key phosphorylation site in LZTS2 protein. LZTS2 exerts an anti-tumor effect by restricting the translocation of the transcription factor β-Catenin into the nucleus, thereby suppressing the Wnt pathway. PLK1 disrupts the interaction between LZTS2 and β-Catenin, resulting in the nuclear accumulation of β-Catenin and the activation of the Wnt pathway. Additionally, we reveal that LZTS2 inhibits the proliferation and migration of LUAD cells, which is rescued by PLK1. Finally, PLK1 inhibitors exhibit a dose-dependent suppression of LUAD cell proliferation and migration. Collectively, this study uncovers the pro-tumorigenic mechanism of PLK1, positioning it as a promising therapeutic target for Wnt-related LUAD., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research, authorship and publication of this article., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: No consensus on a grading system for invasive lung adenocarcinoma had been built over a long period of time. Until October 2020, a novel grading system was proposed to quantify the whole landscape of histologic subtypes and proportions of pulmonary adenocarcinomas. This study aims to develop a deep learning grading signature (DLGS) based on positron emission tomography/computed tomography (PET/CT) to personalize surgical treatments for clinical stage I invasive lung adenocarcinoma and explore the biologic basis under its prediction., Methods: A total of 2638 patients with clinical stage I invasive lung adenocarcinoma from 4 medical centers were retrospectively included to construct and validate the DLGS. The predictive performance of the DLGS was evaluated by the area under the receiver operating characteristic curve (AUC), its potential to optimize surgical treatments was investigated via survival analyses in risk groups defined by the DLGS, and its biological basis was explored by comparing histologic patterns, genotypic alternations, genetic pathways, and infiltration of immune cells in microenvironments between risk groups., Results: The DLGS to predict grade 3 achieved AUCs of 0.862, 0.844, and 0.851 in the validation set (n = 497), external cohort (n = 382), and prospective cohort (n = 600), respectively, which were significantly better than 0.814, 0.810, and 0.806 of the PET model, 0.813, 0.795, and 0.824 of the CT model, and 0.762, 0.734, and 0.751 of the clinical model. Additionally, for DLGS-defined high-risk population, lobectomy yielded an improved prognosis compared to sublobectomy p = 0.085 for overall survival [OS] and p = 0.038 for recurrence-free survival [RFS]) and systematic nodal dissection conferred a superior prognosis to limited nodal dissection (p = 0.001 for OS and p = 0.041 for RFS)., Conclusion: The DLGS harbors the potential to predict the histologic grade and personalize the surgical treatments for clinical stage I invasive lung adenocarcinoma. Its applicability to other territories should be further validated by a larger international study., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Occult nodal metastasis (ONM) plays a significant role in comprehensive treatments of non-small cell lung cancer (NSCLC). This study aims to develop a deep learning signature based on positron emission tomography/computed tomography to predict ONM of clinical stage N0 NSCLC. An internal cohort (n = 1911) is included to construct the deep learning nodal metastasis signature (DLNMS). Subsequently, an external cohort (n = 355) and a prospective cohort (n = 999) are utilized to fully validate the predictive performances of the DLNMS. Here, we show areas under the receiver operating characteristic curve of the DLNMS for occult N1 prediction are 0.958, 0.879 and 0.914 in the validation set, external cohort and prospective cohort, respectively, and for occult N2 prediction are 0.942, 0.875 and 0.919, respectively, which are significantly better than the single-modal deep learning models, clinical model and physicians. This study demonstrates that the DLNMS harbors the potential to predict ONM of clinical stage N0 NSCLC., (© 2023. The Author(s).)

Background: This study, based on multicentre cohorts, aims to utilize computed tomography (CT) images to construct a deep learning model for predicting major pathological response (MPR) to neoadjuvant chemoimmunotherapy in non-small cell lung cancer (NSCLC) and further explore the biological basis under its prediction., Methods: 274 patients undergoing curative surgery after neoadjuvant chemoimmunotherapy for NSCLC at 4 centres from January 2019 to December 2021 were included and divided into a training cohort, an internal validation cohort, and an external validation cohort. ShuffleNetV2x05-based features of the primary tumour on the CT scans within the 2 weeks preceding neoadjuvant administration were employed to develop a deep learning score for distinguishing MPR and non-MPR. To reveal the underlying biological basis of the deep learning score, a genetic analysis was conducted based on 25 patients with RNA-sequencing data., Findings: MPR was achieved in 54.0% (n = 148) patients. The area under the curve (AUC) of the deep learning score to predict MPR was 0.73 (95% confidence interval [CI]: 0.58-0.86) and 0.72 (95% CI: 0.58-0.85) in the internal validation and external validation cohorts, respectively. After integrating the clinical characteristic into the deep learning score, the combined model achieved satisfactory performance in the internal validation (AUC: 0.77, 95% CI: 0.64-0.89) and external validation cohorts (AUC: 0.75, 95% CI: 0.62-0.87). In the biological basis exploration for the deep learning score, a high deep learning score was associated with the downregulation of pathways mediating tumour proliferation and the promotion of antitumour immune cell infiltration in the microenvironment., Interpretation: The proposed deep learning model could effectively predict MPR in NSCLC patients treated with neoadjuvant chemoimmunotherapy., Funding: This study was supported by National Key Research and Development Program of China, China (2017YFA0205200); National Natural Science Foundation of China, China (91959126, 82022036, 91959130, 81971776, 81771924, 6202790004, 81930053, 9195910169, 62176013, 8210071009); Beijing Natural Science Foundation, China (L182061); Strategic Priority Research Program of Chinese Academy of Sciences, China (XDB38040200); Chinese Academy of Sciences, China (GJJSTD20170004, QYZDJ-SSW-JSC005); Shanghai Hospital Development Center, China (SHDC2020CR3047B); and Science and Technology Commission of Shanghai Municipality, China (21YF1438200)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: This study intends to appraise the feasibility of double sleeve lobectomy after neoadjuvant chemotherapy in central non-small-cell lung cancer with bronchovascular aggression., Methods: This retrospective study included non-small-cell lung cancer patients who received double sleeve lobectomy from January 2014 to June 2020. Patients were divided into 2 groups: the neoadjuvant chemotherapy group and the non-neoadjuvant chemotherapy group. Demographic data and perioperative outcomes were compared between these 2 groups., Results: Of the 110 patients who received double sleeve lobectomy during this period, 35 patients (31.8%) received neoadjuvant chemotherapy. Compared with the non-neoadjuvant chemotherapy group, patients who received neoadjuvant chemotherapy were associated with younger age (P = 0.026), smaller pathologic tumour size (P = 0.005), higher forced expiratory volume in 1 s (P = 0.007), higher forced expiratory volume in 1 s of predicted value (P = 0.005) and higher clinical stage (P < 0.001). In the neoadjuvant chemotherapy group, 18 patients (51.4%) attained a partial response and 17 patients (48.6%) achieved stable disease. The postoperative hospital stays (P = 0.042) and chest tube drainage duration (P = 0.030) were longer in the neoadjuvant chemotherapy group and other perioperative performances were similar between these 2 groups. No statistically significant difference was reported in postoperative complications and mortality between these 2 groups., Conclusions: The intraoperative performance and postoperative outcomes of double sleeve lobectomy following neoadjuvant chemotherapy were similar to direct surgery, indicating that double sleeve lobectomy after neoadjuvant chemotherapy is feasible and safe in central lung cancer involving both the pulmonary artery and bronchus., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Altered glutamine metabolism is an important aspect of cancer metabolic reprogramming. The GLS isoform GAC (glutaminase C), the rate-limiting enzyme in glutaminolysis, plays a vital role in cancer initiation and progression. Our previous studies demonstrated that phosphorylation of GAC was essential for its high enzymatic activity. However, the molecular mechanisms for GAC in maintaining its high enzymatic activity and protein stability still need to be further clarified. FAIM/FAIM1 (Fas apoptotic inhibitory molecule) is known as an important anti-apoptotic protein, but little is known about its function in tumorigenesis. Here, we found that knocking down FAIM induced macroautophagy/autophagy through suppressing the activation of the MTOR pathway in lung adenocarcinoma. Further studies demonstrated that FAIM could promote the tetramer formation of GAC through increasing PRKCE/PKCε-mediated phosphorylation. What's more, FAIM also stabilized GAC through sequestering GAC from degradation by protease ClpXP. These effects increased the production of α-ketoglutarate, leading to the activation of MTOR. Besides, FAIM also promoted the association of ULK1 and MTOR and this further suppressed autophagy induction. These findings discovered new functions of FAIM and elucidated an important molecular mechanism for GAC in maintaining its high enzymatic activity and protein stability.

Grainyhead-like 1 (GRHL1) is a transcription factor involved in embryonic development. However, little is known about the biological functions of GRHL1 in cancer. In this study, we found that GRHL1 was upregulated in non-small cell lung cancer (NSCLC) and correlated with poor survival of patients. GRHL1 overexpression promoted the proliferation of NSCLC cells and knocking down GRHL1 inhibited the proliferation. RNA sequencing showed that a series of cell cycle-related genes were altered when knocking down GRHL1. We further demonstrated that GRHL1 could regulate the expression of cell cycle-related genes by binding to the promoter regions and increasing the transcription of the target genes. Besides, we also found that EGF stimulation could activate GRHL1 and promoted its nuclear translocation. We identified the key phosphorylation site at Ser76 on GRHL1 that is regulated by the EGFR-ERK axis. Taken together, these findings elucidate a new function of GRHL1 on regulating the cell cycle progression and point out the potential role of GRHL1 as a drug target in NSCLC.

Introduction: Immune checkpoint inhibitors (ICIs) have become a frontier in the field of clinical technology for advanced non-small cell lung cancer (NSCLC). Currently, the predictive biomarker of ICIs mainly including the expression of PD-L1, TMB, TIICs, MMR and MSI-H. However, there are no official biomarkers to guide the treatment of ICIs and to determine the prognosis. Therefore, it is essential to explore a systematic nomogram to predict the prognosis of ICIs treatment in NSCLC METHODS: In this work, we obtained gene expression and clinical data of NSCLC patients from the TCGA database. Immune-related genes (IRGs) were downloaded from the ImmPort database. The detailed clinical annotation and response data of 240 advanced NSCLC patients who received ICIs treatment were obtained from the cBioPortal for Cancer Genomics. Kaplan-Meier survival analysis was used to perform survival analyses, and selected clinical variables to develop a novel nomogram. The prognostic significance of FGFR4 was validated by another cohort in cBioPortal for Cancer Genomics., Results: 3% of the NSCLC patients harbored FGFR4 mutations. The mutation of FGFR4 were confirmed to be associated with PD-L1, and TMB. Patients harbored FGFR4 mutations were found to have a better prolonged progression-free survival (PFS) to ICIs treatment (FGFR4: P = 0.0209). Here, we built and verified a novel nomogram to predict the prognosis of ICIs treatment for NSCLC patients., Conclusion: Our results showed that FGFR4 could serve as novel biomarkers to predict the prognosis of ICIs treatment of advanced NSCLC. Our systematic prognostic nomogram showed a great potential to predict the prognosis of ICIs for advanced NSCLC patients.

Lung cancer is the leading cause of cancer‑associated mortality worldwide. Parthenolide (PTL), a natural product extracted from the plant Tanacetum parthenium, (a flowering plant in the daisy family, Asteraceae) has been reported to inhibit cancer cell growth, including that of human lung cancer. However, the underlying mechanisms by which PTL exerts its anticancer effect have remained to be fully elucidated. In the present study, Cell Counting Kit‑8 and colony formation assays were used to assess the effect of PTL to inhibit cell proliferation, a wound‑healing assay was performed to assess cell migration and western blot analysis and PCR were employed to reveal the molecular mechanisms by which PTL inhibits human lung carcinoma cell growth. The results indicated that PTL substantially inhibited cell proliferation and migration in two lung cancer cell lines A549 and H1299. Mechanistically, the phosphorylation of insulin‑like growth factor 1 receptor (IGF‑1R), Akt and forkhead box O3α (FoxO3α) was blocked by PTL. Furthermore, IGF‑1‑induced Akt [protein kinase B or (PKB)] and FoxO3α phosphorylation were also inhibited by PTL treatment. In addition, PTL significantly suppressed lung cancer growth in a subcutaneous xenograft mouse model. Taken together, the present in vivo and in vitro results indicate that PTL may suppress lung cancer growth through inhibiting IGF‑1R‑mediated PI3K/Akt/FoxO3α signaling, suggesting that PTL may be an attractive candidate for the treatment of lung cancer.

Aim: To develop an oxidative phosphorylation (OXPHOS)-related gene signature of lung adenocarcinoma (LUAD). Materials & methods: We split The Cancer Genome Atlas LUAD cohort into a training set and a test set; we used the least absolute shrinkage and selection operator Cox method to structure the OXPHOS-related prognostic signature in the training set and verified in the test set and GSE30219 dataset. Meanwhile, the diagnostic model was constructed using the logistic Cox method. Results: The signature consisted of seven genes ( LDHA , CFTR , HSPD1 , SNHG3 , MAP1LC3C , COX6B2 , and TWIST1 ). LUAD patients were divided into high- and low-risk groups, demonstrating good diagnostic and prognostic capabilities. Conclusion: We developed the first-ever OXPHOS-related signature with both prognostic predictive power and diagnostic efficacy.

The gene trim7 encodes at least four isoforms Glycogenin-interacting protein 1 (GNIP1), GNIP2, GNIP3 and Tripartite motif containing 7 (TRIM7). GNIP1, the longest isoform, has been reported acting as an oncogene. However, it is very interesting that TRIM7, the shortest isoform, only 15 amino acids different from GNIP1 in C-terminal, acts in a completely different way from that of GNIP1 in our present study. TRIM7 expression was decreased in tumor compared with adjacent normal tissues, and the level of TRIM7 was negatively correlated with clinical stage of 94 patients with lung cancer. In vitro, TRIM7 dramatically inhibited the proliferation and migration of tumor cells, and promoted cell apoptosis. Further study showed that TRIM7 interacted with p65 via its C-terminal which is different from GNIP1. The interaction between TRIM7 and p65 promoted the ubiquitination of p65 and finally accelerated the degradation of p65 via 26S proteasome. In vivo, the tumor volume and weight were decreased by TRIM7 stable expression. Meanwhile, Ki67 was down-regulated, thyroid transcription factor 1 (TTF-1) and Caspase 3 were up-regulated in TRIM7 overexpression group in xenograft model. It is very impressive that TRIM7t (a truncated TRIM7 without C-terminal sequence that different with GNIP1) had little effect on the tumor growth in vivo. These findings highlight a curious mechanism for negative regulation of NF-kappa B signaling pathway by TRIM7 and demonstrate that TRIM7 would be a potential therapeutic target for lung cancer., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The tripartite motif (TRIM) family is a family of proteins with highly conserved domains. Previous researches have suggested that the members of TRIM family proteins played a crucial role in cancer development and progression. Our study explored the relationship between TRIM35 and non-small cell lung cancer (NSCLC). The study showed that the expression of TRIM35 was increased in NSCLC samples, and patients with high expression of TRIM35 had a poor clinical prognosis. Overexpression of TRIM35 in NSCLC cell line H460 promoted cell proliferation, migration, and invasion, knockdown of TRIM35 produced an opposite result in A549 and H1299 cell lines. In vivo study further confirmed that overexpression of TRIM35 promoted tumor formation. The RNA-seq analysis suggested that TRIM35 might promote lung cancer proliferation, migration, and invasion by regulating cancer-associated functions and signaling pathways. Hence, we identified TRIM35 played a significant role in tumoral growth and was a potential diagnosis and prognosis target for lung cancer., (© 2020 The Author(s).)

Lung adenocarcinoma (LUAD) remains the leading cause of cancer-related deaths worldwide. Increasing evidence suggests that circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) can regulate target gene expression and participate in tumor genesis and progression. However, hub driving genes and regulators playing a potential role in LUAD progression have not been fully elucidated yet. Based on data from The Cancer Genome Atlas database, 2837 differentially expressed genes, 741 DE-regulators were screened by comparing cancer tissues with paracancerous tissues. Then, 651 hub driving genes were selected by the topological relation of the protein-protein interaction network. Also, the target genes of DE-regulators were identified. Moreover, a key gene set containing 65 genes was obtained from the hub driving genes and target genes intersection. Subsequently, 183 hub regulators were selected based on the analysis of node degree in the ceRNA network. Next, a comprehensive analysis of the subgroups and Wnt, mTOR, and MAPK signaling pathways was conducted to understand enrichment of the subgroups. Survival analysis and a receiver operating characteristic curve analysis were further used to screen for the key genes and regulators. Furthermore, we verified key molecules based on external database, LRRK2, PECAM1, EPAS1, LDB2, and HOXA11-AS showed good results. LRRK2 was further identified as promising biomarker associated with CNV alteration and various immune cells' infiltration levels in LUAD. Overall, the present study provided a novel perspective and insight into hub driving genes and regulators in LUAD, suggesting that the identified signature could serve as an independent prognostic biomarker., (© 2020 The Author(s).)

Lung cancer is one of the most commonly diagnosed malignancies worldwide. Cryptotanshinone (CPT) is a diterpene quinone compound extracted from natural plants and has been reported to have anticancer effects in several cancers including human lung cancer. However, the mechanism by which CPT acts to prevent lung cancer cell growth is largely unknown. In the present study, by using MTT assay, colony formation assay, wound healing and western blotting assays, the effects of CPT on the cell proliferation and migration of human lung cancer cells and the potential cellular signaling mechanisms were investigated. The data demonstrated that CPT exhibited anti-proliferative effects against A549 and H1299 cells. In parallel, the migration of A549 cells was also markedly inhibited by CPT treatment. Further study indicated that CPT not only inhibited the basal phosphorylation level of insulin-like growth factor 1 receptor (IGF-1R) and RAC-alpha serine/threonine-protein kinase (Akt), but also blocked IGF-1 induced IGF-1R and Akt phosphorylation. Finally, it was demonstrated that pretreatment with CPT inhibited IGF-1 induced cell proliferation of A549 and H1299 cells. In conclusion, the results of the present study indicated that CPT inhibits the proliferation and migration of lung cancer cells via a mechanism that involves inhibiting the IGF-1R-mediated phosphoinositide 3-kinase/Akt signaling pathway. The data provides evidence that CPT could be developed as a potential therapeutic agent for the treatment of lung cancer.

Glutamine metabolism plays an important role in cancer development and progression. Glutaminase C (GAC), the first enzyme in glutaminolysis, has emerged as an important target for cancer therapy and many studies have focused on the mechanism of enhanced GAC expression in cancer cells. However, little is known about the post-translational modification of GAC. Here, we report that phosphorylation is a crucial post-translational modification of GAC, which is responsible for the higher glutaminase activity in lung tumor tissues and cancer cells. We identify the key Ser314 phosphorylation site on GAC that is regulated by the NF-κB-PKCε axis. Blocking Ser314 phosphorylation by the S314A mutation in lung cancer cells inhibits the glutaminase activity, triggers genetic reprogramming, and alleviates tumor malignancy. Furthermore, we find that a high level of GAC phosphorylation correlates with poor survival rate of lung cancer patients. These findings highlight a previously unappreciated mechanism for activation of GAC by phosphorylation and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation.

SUN2, a key component of LINC (linker of nucleoskeleton and cytoskeleton) complex located at the inner nuclear membrane, plays unknown role in lung cancer. We found that SUN2 expression was decreased in lung cancer tissue compared with paired normal tissues and that higher SUN2 levels predicted better overall survival and first progression survival. Overexpression of SUN2 inhibits cell proliferation, colony formation and migration in lung cancer, whereas knockdown of SUN2 promotes cell proliferation and migration. Additionally, SUN2 increases the sensitivity of lung cancer to cisplatin by inducing cell apoptosis. Mechanistically, we showed that SUN2 exerts its tumor suppressor functions by decreasing the expression of GLUT1 and LDHA to inhibit the Warburg effect. Finally, our results provided evidence that SIRT5 acts, at least partly, as a negative regulator of SUN2.Taken together, our findings indicate that SUN2 is a key component in lung cancer progression by inhibiting the Warburg effect and that the novel SIRT5/SUN2 axis may prove to be useful for the development of new strategies for treating the patients with lung cancer.

Lipocalin 2 (LCN2), a multifunctional secretory protein known as neutrophil gelatinase-associated lipocalin (NGAL), is expressed in a variety of cancers. However, little is known about the biological functions of NGAL in the development of lung adenocarcinoma. In the present study, we primarily found that NGAL expression was up-regulated in human lung adenocarcinoma tissues. Additionally, depletion of NGAL expression decreased the ability of cell proliferation and induced cell apoptosis. Furthermore, with the addition of N-acetylcysteine, a scavenger of reactive oxygen species (ROS), it was found that NGAL depletion was sufficient to cause apoptosis of lung adenocarcinoma cells by generating ROS through the inhibition of the nuclear factor E2-related factor 2/heme oxygenase-1 anti-oxidant pathway. Finally, the effect of NGAL down-regulation on the growth of human lung adenocarcinoma was determined in BALB/c nude mice. These findings demonstrate that NGAL may be a potential therapy target for patients with lung adenocarcinoma., (© The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.)