bims-meluca 2021-02-07 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–02–07
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

SAM68 promotes tumorigenesis in lung adenocarcinoma by regulating metabolic conversion via PKM alternative splicing.
Evaluation of the prognostic values of solute carrier (SLC) family 39 genes for patients with lung adenocarcinoma.
Protein Glycopatterns in Bronchoalveolar Lavage Fluid as Novel Potential Biomarkers for Diagnosis of Lung Cancer.
Reversion from Methionine Addiction to Methionine Independence Results in Loss of Tumorigenic Potential of Highly-malignant Lung-cancer Cells.
Dysregulation of ferroptosis may involve in the development of non-small-cell lung cancer in Xuanwei area.
Prognostic significance of genetic variants in GLUT1 in stage III non-small cell lung cancer treated with radiotherapy.
Plasma metabolomic profile associated with fatigue in cancer patients.

Theranostics. 2021 ;11(7): 3359-3375

SAM68 promotes tumorigenesis in lung adenocarcinoma by regulating metabolic conversion via PKM alternative splicing.

Song Zhu, Weiping Chen, Jizhong Wang, Ling Qi, Huilin Pan, Zhengfu Feng, Dongbo Tian.

  Background: A metabolic "switch" from oxidative phosphorylation to glycolysis provides tumor cells with energy and biosynthetic substrates, thereby promoting tumorigenesis and malignant progression. However, the mechanisms controlling this metabolic switch in tumors is not entirely clear. Methods: Clinical specimens were used to determine the effect of SAM68 on lung adenocarcinoma (LUAD) tumorigenesis and metastasis, and mouse models and molecular biology assays were performed to elucidate the function and underlying mechanisms in vitro and in vivo. Results: SAM68 mRNA levels were higher in LUAD tissue than in normal lung tissue, indicating that SAM68 expression is upregulated in LUAD. Patients with LUAD with SAM68 high (n = 257) had a higher frequency of tumor recurrence (p = 0.025) and recurrence-free survival (p = 0.013) than did those with SAM68 low (n = 257). Patients with SAM68 high mRNA levels (n = 257) were at a higher risk for cancer-related death (p = 0.006), and had shorter overall survival (p = 0.044) than did those with SAM68 low. SAM68 promotes tumorigenesis and metastasis of LUAD cells in vitro and in vivo by regulating the cancer metabolic switch. SAM68 drives cancer metabolism by mediating alternative splicing of pyruvate kinase (PKM) pre-mRNAs, and promoting the formation of PKM2. Mechanistically, SAM68 increased the binding of the splicing repressor hnRNP A1 to exon 9 of PKM, thereby enhancing PKM2 isoform formation and PKM2-dependent aerobic glycolysis and tumorigenesis. Conclusions: SAM68 promotes LUAD cell tumorigenesis and cancer metabolic programming via binding of the 351-443 aa region of SAM68 to the RGG motif of hnRNP A1, driving hnRNP A1-dependent PKM splicing, contributing to increased oncogene PKM2 isoform formation and inhibition of PKM1 isoform formation. SAM68 is therefore a promising therapeutic target for the treatment of LUAD.

Keywords:  SAM68; alternative splicing; lung adenocarcinoma; metabolism conversion; tumorigenesis

DOI:  https://doi.org/10.7150/thno.51360
Aging (Albany NY). 2021 Feb 01. 12

Evaluation of the prognostic values of solute carrier (SLC) family 39 genes for patients with lung adenocarcinoma.

Heng Zhou, Yaoqi Zhu, Huizhong Qi, Liang Liang, Hao Wu, Jingping Yuan, Qingyong Hu.

   BACKGROUND: Lung cancer is the first fatality rate of cancer-related death worldwide. This study aimed to evaluate the solute carrier family 39 (SLC39A) genes as biological markers associated with the prognosis of lung adenocarcinoma (LUAD).
METHODS AND MATERIALS: MRNA expression of SLC39A genes in non-small cell lung cancer (NSCLC) was analyzed using UCSC database. We investigated the overall survival (OS) of SLC39A genes in patients with NSCLC as the only prognostic indicator using the Kaplan-Meier plotter. CERES score obtained from the Project Achilles was used to perform the survival analysis. Crystal violet-glutaraldehyde solution staining and CCK-8 assay were used to determine colony formation and cell viability, respectively.
RESULTS: For patients with lung squamous cell carcinoma, only high expression of SLC39A3, SLC39A4 and SLC39A7 have significant affections to the prognosis. But for patients with LUAD, 11 out of 14 SLC39A genes were significantly associated with prognostic values. Additional analysis indicated that SLC39A7 played an essential role for cell survival of LUAD. Furthermore, SLC39A7 high expression in LUAD was associated with current smoking.
CONCLUSIONS: Our findings indicated that SLC39A groups were significantly associated with prognosis of LUAD. The SLC39A7 gene was significantly linked with survival and growth of LUAD cells.

Keywords:  LUAD; NSCLC; SLC39A; SLC39A7; prognosis

DOI:  https://doi.org/10.18632/aging.202452
Front Oncol. 2020 ;10 568433

Protein Glycopatterns in Bronchoalveolar Lavage Fluid as Novel Potential Biomarkers for Diagnosis of Lung Cancer.

Lina Liu, Dan Li, Jian Shu, Li Wang, Fan Zhang, Chen Zhang, Hanjie Yu, Mingwei Chen, Zheng Li, Xuan Guo.

  Lung cancer is one of the most prevalent and life-threatening neoplasias worldwide due to the deficiency of ideal diagnostic biomarkers. Although aberrant glycosylation has been observed in human serum and tissue, little is known about the alterations in bronchoalveolar lavage fluid (BALF) that are extremely associated with lung cancer. In this study, our aim was to systematically investigate and assess the alterations of protein glycopatterns in BALF and possibility as biomarkers for diagnosis of lung cancer. Here, lectin microarrays and blotting analysis were utilized to detect the differential expression of BALF glycoproteins from patients with 80 adenocarcinomas (ADC), 77 squamous carcinomas (SCC), 51 small cell lung cancer (SCLC), and 73 benign pulmonary diseases (BPD). These 281 specimens were then randomly divided into a training cohort and validation cohort for constructing and verifying the diagnostic models based on the glycopattern abundances. Moreover, an independent test was performed with 120 newly collected BALF samples enrolled in the double-blind cohort to further assess the clinical application potential of the diagnostic models. According to the results, there were 15 (e.g., PHA-E, EEL, and BPL) and 14 lectins (e.g., PTL-II, LCA, and SJA) that individually showed significant variations in different types and stages of lung cancer compared to BPD. Notably, the diagnostic models achieved better discriminate power in the validation cohort and exhibited high accuracies of 0.917, 0.864, 0.712, 0.671, and 0.781 in the double-blind cohort for the diagnosis of lung cancer, early stage lung cancer, ADC, SCC, and SCLC, respectively. Taken together, the present study revealed that the abnormally altered protein glycopatterns in BALF are expected to be novel potential biomarkers for the identification and early diagnosis of lung cancer, which will contribute to explain the mechanism of the development of lung cancer from the perspective of glycobiology.

Keywords:  bronchoalveolar lavage fluid; diagnostic model; lectin microarray; lung cancer; protein glycosylation

DOI:  https://doi.org/10.3389/fonc.2020.568433
Anticancer Res. 2021 Feb;41(2): 641-643

Reversion from Methionine Addiction to Methionine Independence Results in Loss of Tumorigenic Potential of Highly-malignant Lung-cancer Cells.

Jun Yamamoto, Yusuke Aoki, Qinghong Han, Norihiko Sugisawa, Y U Sun, Kazuyuki Hamada, Hiroto Nishino, Sachiko Inubushi, Kentaro Miyake, Ryusei Matsuyama, Michael Bouvet, Itaru Endo, Robert M Hoffman.

   BACKGROUND/AIM: Methionine addiction, a fundamental and general hallmark of cancer, is due to the excess use of methionine for transmethylation, and is described as the Hoffman-effect. Methionine-addicted cancer cells can revert at low frequency to methionine independence when selected under methionine-restriction. We report here that highly-malignant methionine-addicted H460 human lung-cancer cells, when selected for methionine independence, have greatly-reduced tumorigenic potential.
MATERIALS AND METHODS: Methionine-addicted H460 parental cancer cells and methionine-independent revertant H460-R1 cells were injected in nude mice subcutaneously.
RESULTS: When the parental H460 methionine-addicted cells were injected in nude mice at 2.5×105, 1×105 and 5×104, the cells could form tumors. In contrast, the H460-R1 methionine-independent revertant cells could not form tumors when the above-listed cell numbers were injected in nude mice.
CONCLUSION: There is a tight linkage between methionine addiction and malignancy.

Keywords:  Cancer; H460; lung cancer; methionine addiction; methionine independence; reversion; tumorigenicity

DOI:  https://doi.org/10.21873/anticanres.14815
J Cell Mol Med. 2021 Feb 02.

Dysregulation of ferroptosis may involve in the development of non-small-cell lung cancer in Xuanwei area.

Guangjian Li, Jiapeng Yang, Guangqiang Zhao, Zhenghai Shen, Kaiyun Yang, Linwei Tian, Qinghua Zhou, Ying Chen, Yunchao Huang.

  The Xuanwei area of Yunnan Province, China, is one of the regions suffering from the highest occurrence and mortality rate of lung cancer in the world. Local residents tend to use bituminous coal as domestic fuel, which causes serious indoor air pollution and is established as the main carcinogen. After the local government carried out furnace and stove reform work, lung cancer rate including incidence and mortality among residents remains high. We herein wonder if there are specific mechanisms at protein level for the development of non-small-cell lung cancer (NSCLC) in this area. We investigated the changes of protein profiling in tumour of the patients from Xuanwei area. Tandem mass tag (TMT) was employed to screen the differential proteins between carcinoma and para-carcinoma tissues. We identified a total of 422 differentially expressed proteins, among which 162 proteins were significantly up-regulated and 260 were downregulated compared to para-carcinoma tissues. Many of the differentially expressed proteins were related to extracellular matrix (ECM)-receptor interaction, focal adhesion, PI3K/AKT pathway and ferroptosis. Further experiments on the two differential proteins, thioredoxin 2 (TXN2) and haptoglobin (HP), showed that the change of their expressions could make the lung cancer cell lines more resistant to erastin or RSL-induced ferroptosis in vitro, and promote the growth of tumour in nude mice. In conclusion, this study revealed that aberrant regulation of ferroptosis may involve in the development of lung cancer in Xuanwei area.

Keywords:  Xuanwei; ferroptosis; haptoglobin; lung cancer; thioredoxin

DOI:  https://doi.org/10.1111/jcmm.16318
Thorac Cancer. 2021 Jan 31.

Prognostic significance of genetic variants in GLUT1 in stage III non-small cell lung cancer treated with radiotherapy.

Min Kyu Kang, Shin Yup Lee, Jin Eun Choi, Sun Ah Baek, Sook Kyung Do, Jeong Eun Lee, Jongmoo Park, Seung Soo Yoo, Sunha Choi, Kyung Min Shin, Ji Yun Jeong, Jae Yong Park.

   BACKGROUND: To examine the impact of polymorphisms of glucose transporter 1 (GLUT1) gene on the prognosis of patients with stage III non-small cell lung cancer (NSCLC) who received radiotherapy.
METHODS: Five single nucleotide polymorphisms (SNPs) (rs4658C>G, rs1385129G>A, rs3820589A>T, rs3806401A>C and rs3806400C>T) in GLUT1 gene were evaluated in 90 patients with pathologically confirmed stage III NSCLC. A total of 21 patients were treated with radiotherapy alone, 25 with sequential chemoradiotherapy, and 44 with concurrent chemoradiotherapy. The association of the genetic variations of five SNPs with overall survival (OS) and progression-free survival (PFS) was analyzed.
RESULTS: Two SNPs (rs1385129 and rs3806401) were significant risk factors for OS. Three SNPs (rs1385129, rs3820589 and rs3806401) were in linkage disequilibrium. In Cox proportional hazard models, GAA haplotype was a good prognostic factor for OS (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.39-0.81, p = 0.002) and PFS (HR = 0.68, 95% CI: 0.47-0.99, p = 0.043), compared to variant haplotypes. The GAA/GAA diplotype was observed in 46.7% of patients; these patients showed significantly better OS (HR = 0.38, 95% CI: 0.22-0.65, p < 0.001) and PFS (HR = 0.51, 95% CI: 0.31-0.85, p = 0.009) compared to those with other diplotypes.
CONCLUSIONS: These results suggest that polymorphisms of GLUT1 gene could be used as a prognostic marker for patients with stage III NSCLC treated with radiotherapy.

Keywords:  GLUT1; non-small cell lung cancer; polymorphisms; radiotherapy

DOI:  https://doi.org/10.1111/1759-7714.13851
Cancer Med. 2021 Feb 03.

Plasma metabolomic profile associated with fatigue in cancer patients.

Li Rebekah Feng, Jennifer J Barb, Jeniece Regan, Leorey N Saligan.

   BACKGROUND: Metabolomics is the newest -omics methodology and allows for a functional snapshot of the biochemical activity and cellular state. The goal of this study is to characterize metabolomic profiles associated with cancer-related fatigue, a debilitating symptom commonly reported by oncology patients.
METHODS: Untargeted ultrahigh performance liquid chromatography/mass spectrometry metabolomics approach was used to identify metabolites in plasma samples collected from a total of 197 participants with or without cancer. Partial least squares-discriminant analysis (PLS-DA) was used to identify discriminant metabolite features, and diagnostic performance of selected classifiers was quantified using area under the receiver operating characteristics (AUROC) curve analysis. Pathway enrichment analysis was performed using Fisher's exact test and the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway database.
FINDINGS: The global metabolomics approach yielded a total of 1120 compounds of known identity. Significant metabolic pathways unique to fatigued cancer versus control groups included sphingolipid metabolism, histidine metabolism, and cysteine and methionine metabolism. Significant pathways unique to non-fatigued cancer versus control groups included inositol phosphate metabolism, primary bile acid biosynthesis, ascorbate and aldarate metabolism, starch and sucrose metabolism, and pentose and glucuronate interconversions. Pathways shared between the two comparisons included caffeine metabolism, tyrosine metabolism, steroid hormone biosynthesis, sulfur metabolism, and phenylalanine metabolism.
CONCLUSIONS: We found significant metabolomic profile differences associated with cancer-related fatigue. By comparing metabolic signatures unique to fatigued cancer patients with metabolites associated with, but not unique to, fatigued cancer individuals (overlap pathways) and metabolites associated with cancer but not fatigue, we provided a broad view of the metabolic phenotype of cancer-related fatigue.

Keywords:  cancer fatigue; cancer-related fatigue; fatigue; metabolomics

DOI:  https://doi.org/10.1002/cam4.3749