bims-meluca 2021-10-10 papers

Anal Bioanal Chem. 2021 Oct 07.

Metabolic network-based identification of plasma markers for non-small cell lung cancer.

Linling Guo, Linrui Li, Zhiyun Xu, Fanchen Meng, Huimin Guo, Peijia Liu, Peifang Liu, Yuan Tian, Fengguo Xu, Zunjian Zhang, Shuai Zhang, Yin Huang.

Metabolic markers, offering sensitive information on biological dysfunction, play important roles in diagnosing and treating cancers. However, the discovery of effective markers is limited by the lack of well-established metabolite selection approaches. Here, we propose a network-based strategy to uncover the metabolic markers with potential clinical availability for non-small cell lung cancer (NSCLC). First, an integrated mass spectrometry-based untargeted metabolomics was used to profile the plasma samples from 43 NSCLC patients and 43 healthy controls. We found that a series of 39 metabolites were altered significantly. Relying on the human metabolic network assembled from Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we mapped these differential metabolites to the network and constructed an NSCLC-related disease module containing 23 putative metabolic markers. By measuring the PageRank centrality of molecules in this module, we computationally evaluated the network-based importance of the 23 metabolites and demonstrated that the metabolism pathways of aromatic amino acids and long-chain fatty acids provided potential molecular targets of NSCLC (i.e., IL4l1 and ACOT2). Combining network-based ranking and support-vector machine modeling, we further found a panel of eight metabolites (i.e., pyruvate, tryptophan, and palmitic acid) that showed a high capability to differentiate patients from controls (accuracy > 97.7%). In summary, we present a meaningful network method for metabolic marker discovery and have identified eight strong candidate metabolites for NSCLC diagnosis.

Keywords: Centrality; Lung cancer; Mass spectrometry; Metabolomics; Network medicine

DOI: https://doi.org/10.1007/s00216-021-03699-5

Rep Biochem Mol Biol. 2021 Jul;10(2): 327-333

Association Between NOX4 And Nrf2 Genes in Non-Small-Cell Lung Carcinoma: A Case-Control Study.

Nasim Bakhtiyari, Akbar Sharifi, Younes Aftabi, Neda Gilani, Venus Zafari, Atefeh Ansarin, Ensiyeh Seyedrezazadeh.

Background: Epithelial malignancy in lung cancer, which is initiated with myofibroblast differentiation and remodeling, promotes hypoxia and intracellular ROS generation most affected by the prototypical enzyme, NADPH oxidase 4 (NOX4). In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a critical transcription factor by stimulating antioxidant proteins as redox homeostasis regulators. The aim of this study was to investigate a possible correlation between lung tissue NOX4 and Nrf2 genes (NOX4 and Nrf2) mRNA expression and bronchoalveolar lavage fluid (BALF) protein expression in non-small-cell lung carcinoma (NSCLC) patients.
Methods: Samples from 25 patients with various NSCLC types and stages and 20 healthy controls were collected. NOX4 and Nrf2 mRNA were measured by qRT-PCR, and protein by western blot analysis.
Results: NOX4 mRNA and protein expression was significantly up-regulated in NSCLC patients' lung tissues and BALFs (p= 0.03 and 0.01, respectively). In addition, by adjusting for age, sex, and NSCLC types and stages, a significant and positive correlation was observed between NOX4 and Nrf2 mRNA expression (r= 0.927, p= 0.001). This was also true when not adjusted as above (r= 0.944, p< 0.001).
Conclusion: NOX4 mRNA and protein expression is significantly up-regulated in NSCLC patients' lung tissues and BALFs, and NOX4 and Nrf2 mRNA expression is positively correlated in NSCLC tissues.

Keywords: Gene expression; NOX4; Non-small-cell lung cancer; Nrf2

DOI: https://doi.org/10.52547/rbmb.10.2.327

J Clin Invest. 2021 Oct 05. pii: e152067. [Epub ahead of print]

RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11.

Ferroptosis, an iron-dependent non-apoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here we reported that the RNA binding protein RBMS1 participated in lung cancer development through mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 was a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3'- and 5'-UTRs of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake and promotes ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potentials and clinical values.

Keywords: Cell Biology; Lung cancer; Molecular biology; Oncology; Translation

DOI: https://doi.org/10.1172/JCI152067

Eur Rev Med Pharmacol Sci. 2021 Sep;pii: 26783. [Epub ahead of print]25(18): 5636-5652

Prognostic nutritional index as a prognostic factor in lung cancer patients receiving chemotherapy: a systematic review and meta-analysis.

Q Zhang, J Bao, Z-Y Zhu, M-X Jin.

OBJECTIVE: Lung cancer is one of the leading causes of morbidity and mortality in the world. In the past decade, numerous studies focus on the prognostic nutritional index (i.e., a measure of serum albumin and lymphocyte in peripheral circulation) as a possible biomarker to predict the survival outcomes in cancer patients undergoing chemotherapy. Prognostic nutritional index can reliably predict the survivability outcomes by effectively quantifying the nutritional and immunological status of cancer patients. To date, only one review has attempted to evaluate the impact of the prognostic nutritional index on the survival outcomes in lung cancer patients with certain limitations. The goal of the present systematic review and meta-analysis is to bridge the gap in the literature and evaluate the capacity of the prognostic nutritional index for predicting the survivability outcomes in lung cancer patients undergoing chemotherapy. The aim of the study is to evaluate the impact of prognostic nutritional index scoring on survival outcomes in lung cancer patients undergoing chemotherapy.
MATERIALS AND METHODS: A systematic academic literature search was performed based on the PRISMA guidelines across Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE databases. A random-effect meta-analysis was performed to evaluate the impact of prognostic nutritional index scoring (i.e., high/low) on survival outcomes (i.e., progression-free survival, overall survival) in lung cancer patients undergoing chemotherapy.
RESULTS: From 963 studies, 16 eligible studies with 4250 lung cancer patients (62.32 ± 5.08 years) undergoing chemotherapy were included. Our meta-analysis revealed worse mortality outcomes in terms of progression-free survival (HR: 1.31) and overall survival (1.21) for the group with a low prognostic nutritional index score as compared to the group with a high prognostic nutritional index score in lung cancer patients undergoing chemotherapy. Subsequent subgroup analyses further demonstrated markedly worse outcomes for progression-free survival (1.32) and overall survival (1.52) in non-small lung cancer patients with lower prognostic nutritional index scores.
CONCLUSIONS: We provide preliminary evidence suggesting that lower prognostic nutrition index scores are associated with worse survivability outcomes (progression-free survival and overall survival) in lung cancer patients undergoing chemotherapy. We also show that lower prognostic nutrition index scores correlate with even worse survival outcomes in patients with non-small lung cancer histological subtype of lung cancer. These findings should help clinicians to stratify the risks associated with the chemotherapeutic management of lung cancer patients.

DOI: https://doi.org/10.26355/eurrev_202109_26783

J Thorac Oncol. 2021 Sep 30. pii: S1556-0864(21)03187-7. [Epub ahead of print]

Comprehensive Analysis of TP53 and KEAP1 Mutations and their Impact on Survival in Localized and Advanced Stage Non-Small Cell Lung Cancer.

Mohamed Mahde Saleh, Matthias Scheffler, Sabine Merkelbach-Bruse, Andreas Hans Scheel, Bastian Ulmer, Jürgen Wolf, Reinhard Buettner.

INTRODUCTION: TP53 and KEAP1 are frequently mutated in non-small cell lung cancer (NSCLC) but their prognostic value is ambiguous, particularly in localized stage tumours.
PATIENTS AND METHODS: This retrospective cohort study included 6297 NSCLC patients, who were diagnosed between November 1998 and February 2020. The primary endpoint was overall survival (OS). Patients were diagnosed in a central pathology laboratory as part of the Network Genomic Medicine (NGM) collaboration, encompassing more than 300 lung cancer treating oncology centres in Germany. All patients underwent molecular testing including targeted NGS panel sequencing and in-situ hybridization.
RESULTS: 6297 NSCLC patients were analysed. In 1518 surgically treated patients (UICC I-IIIA), truncating TP53 mutations and KEAP1 mutations were independent negative prognostic markers in multivariable analysis (HRTP53truncating 1.43 [95% CI 1.07 to 1.91]; P=0.015, HRKEAP1mut 1.68 [95% CI 1.24 to 2.26]; P=0.001). Consistently, these mutations were associated with shorter disease-free survival (DFS). In 4779 advanced stage (UICC IIIB-IV) patients, TP53 mutations did not predict outcome in univariable analysis. In contrast, KEAP1 mutations remained a negative prognostic factor (HRKEAP1mut 1.40 [95% CI 1.23 to 1.61], P<0.001) in patients with advanced stage tumours. Further, KEAP1 mutant tumours with co-occurring TP53 missense mutations revealed longer OS than KEAP1 mutant tumours with wildtype or truncating TP53 mutations.
CONCLUSIONS: This study found that TP53 and KEAP1 mutations were prognostic for localized and advanced NSCLC. The increased relative hazard of harbouring TP53 or KEAP1 mutations was comparable to an increase in one UICC stage. Our data suggests that molecular stratification based on TP53 and KEAP1 mutation status should be implemented for localized and advanced stage NSCLC to optimize and modify clinical-decision making.

Keywords: KEAP1; Non-small cell lung cancer (NSCLC); TP53; biomarkers; prognosis

DOI: https://doi.org/10.1016/j.jtho.2021.08.764

Oxid Med Cell Longev. 2021 ;2021 8457521

Ferroptosis: A New Promising Target for Lung Cancer Therapy.

Rui Xiong, Ruyuan He, Bohao Liu, Wenyang Jiang, Bo Wang, Ning Li, Qing Geng.

Ferroptosis is a new type of regulatory cell death that differs from autophagy, apoptosis, necrosis, and pyroptosis; it is caused primarily by the accumulation of iron and lipid peroxides in the cell. Studies have shown that many classical signaling pathways and biological processes are involved in the process of ferroptosis. In recent years, investigations have revealed that ferroptosis plays a crucial role in the progression of tumors, especially lung cancer. In particular, inducing ferroptosis in cells can inhibit the growth of tumor cells, thereby reversing tumorigenesis. In this review, we summarize the characteristics of ferroptosis from its underlying basis and role in lung cancer and provide possible applications for it in lung cancer therapies.

DOI: https://doi.org/10.1155/2021/8457521