bims-meluca 2022-01-16 papers

Cells. 2022 Jan 05. pii: 176. [Epub ahead of print]11(1):

Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer.

Hyunmin Lee, Feng Cai, Neil Kelekar, Nipun K Velupally, Jiyeon Kim.

In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and tumor suppressor STK11 (also known as LKB1) confer an aggressive malignant phenotype, an unfavourability towards immunotherapy, and overall poor prognoses in patients. In a previous study, we showed that murine KRAS/LKB1 co-mutant tumors and human co-mutant cancer cells have an enhanced dependence on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP), which could be targeted to reduce survival of KRAS/LKB1 co-mutants. Here, we found that KRAS/LKB1 co-mutant cells also exhibit an increased dependence on N-acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced KRAS/LKB1 co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in KRAS/LKB1 co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC.

Keywords: KRAS and LKB1 co-mutations; O-GlcNAcylation; cancer metabolism; glycosylation; metabolic vulnerability; non-small cell lung cancer; the hexosamine biosynthesis pathway

DOI: https://doi.org/10.3390/cells11010176

Int J Biol Sci. 2022 ;18(2): 522-535

LncRNA FAM83A-AS1 facilitates tumor proliferation and the migration via the HIF-1α/ glycolysis axis in lung adenocarcinoma.

Zhencong Chen, Zhengyang Hu, Qihai Sui, Yiwei Huang, Mengnan Zhao, Ming Li, Jiaqi Liang, Tao Lu, Cheng Zhan, Zongwu Lin, Fenghao Sun, Qun Wang, Lijie Tan.

Background: Lung adenocarcinoma (LUAD), the major subtype of lung cancer, is among the leading cause of cancer-related death worldwide. Energy-related metabolic reprogramming metabolism is a hallmark of cancer shared by numerous cancer types, including LUAD. Nevertheless, the functional pathways and molecular mechanism by which FAM83A-AS1 acts in metabolic reprogramming in lung adenocarcinoma have not been fully elucidated. Methods: We used transwell, wound-healing scratch assay, and metabolic assays to explore the effect of FAM83A-AS1 in LUAD cell lines. Western blotting, Co-IP assays, and ubiquitination assays were used to detect the effects of FAM83A-AS1 on HIF-1α expression, degradation, and its binding to VHL. Moreover, an in vivo subcutaneous tumor formation assay was used to detect the effect of FAM83A-AS1 on LUAD. Results: Herein, we identified FAM83A-AS1 as a metabolism-related lncRNA, which was highly correlated with glycolysis, hypoxia, and OXPHOS pathways in LUAD patients using bioinformatics analysis. In addition, we uncovered that FAM83A-AS1 could promote the migration and invasion of LUAD cells, as well as influence the stemness of LUAD cells in vivo and vitro. Moreover, FAM83A-AS1 was shown to promote glycolysis in LUAD cell lines in vitro and in vivo, and was found to influence the expression of genes related to glucose metabolism. Besides, we revealed that FAM83A-AS1 could affect glycolysis by regulating HIF-1α degradation. Finally, we found that FAM83A-AS1 knockdown could inhibit tumor growth and suppress the expression of HIF-1α and glycolysis-related genes in vivo. Conclusion: Our study demonstrates that FAM83A-AS1 contributes to LUAD proliferation and stemness via the HIF-1α/glycolysis axis, making it a potential biomarker and therapeutic target in LUAD patients.

Keywords: FAM83A-AS1; HIF-1α/glycolysis axis; Lung adenocarcinoma (LUAD); Metabolic reprogramming

DOI: https://doi.org/10.7150/ijbs.67556

Transl Lung Cancer Res. 2021 Nov;10(11): 4200-4208

Assessing the association of diabetes with lung cancer risk.

Amanda Leiter, Antonios Charokopos, Stacyann Bailey, Emily J Gallagher, Fred R Hirsch, Derek LeRoith, Juan P Wisnivesky.

Background: Diabetes is a well-established risk factor for many cancers, but its relationship with lung cancer incidence remains unclear. In this study, we aimed to assess if diabetes is independently associated with lung cancer risk and histology subtype among participants in a screening study.
Methods: In a retrospective cohort study using data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) study, we assessed the association of self-reported diabetes with lung cancer incidence using Poisson regression while adjusting for other established risk factors in the PLCOM2012, a validated lung cancer prediction model. The adjusted association of diabetes and lung cancer cell type was evaluated using nominal regression. Stratified analyses were also conducted according to sex, smoking history, and body mass index categories.
Results: Overall, 140,395 participants were included in our analysis. Diabetes was not significantly associated with lung cancer incidence [incidence rate ratio (IRR): 1.03, 95% confidence interval (CI): 0.91-1.17]. Similarly, stratified analyses also did not show significant associations between diabetes and lung cancer risk (all P values >0.05). We found no significant difference in the distribution of lung cancer histology in participants with vs. without diabetes (P=0.30).
Conclusions: Diabetes was not an independent risk factor for lung cancer in a large cohort of PLCO participants. We did not observe differences in histology according to diabetes status. These results suggest that patients with diabetes do not need more aggressive lung cancer screening. Future research including more detailed metabolic parameters may further elucidate the relationship between metabolic disease and lung cancer risk.

Keywords: Lung neoplasms; early detection of cancer; lung cancer incidence; lung cancer screening; metabolic disease and cancer

DOI: https://doi.org/10.21037/tlcr-21-601

J Mol Histol. 2022 Jan 14.

Glucose-6-phosphate dehydrogenase promotes the proliferation and migration of lung adenocarcinoma cells via the STAT3 signaling pathway.

Weidong Wu, Fengqiang Yu, Nanding Yu, Yong Zhu, Weihan Wu, Pengqiang Gao, Chun Chen.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, and the leading cause of cancer-related deaths worldwide. G6PD has been reported to enhance the progression of various tumors by regulating the intracellular redox state and mediating nucleic acid synthesis. However, the biological role and molecular mechanism of G6PD in LUAD remain largely unknown. In this study, we found that G6PD was significantly upregulated in LUAD specimens and cell lines, and that the high levels of G6PD expression were closely associated with a poor prognosis for LUAD patients. Moreover, we found that G6PD significantly promoted the proliferation and migration of LUAD cells in vitro, and overexpression of G6PD also play a role of facilitating tumorigenesis in in vivo experiments. Mechanistically, the STAT3 signaling pathway was significantly activated by G6PD-mediated LUAD progression. Overall, our results suggest that G6PD could serve as a novel prognostic marker and therapeutic target for treating LUAD.

Keywords: G6PD; Lung adenocarcinoma; Migration; Proliferation; STAT3

DOI: https://doi.org/10.1007/s10735-021-10045-7

Int J Gen Med. 2021 ;14 10467-10481

A Novel Prognostic and Predictive Signature for Lung Adenocarcinoma Derived from Combined Hypoxia and Infiltrating Immune Cell-Related Genes in TCGA Patients.

Xiaofeng Wu, Jing Zhu, Wei Liu, Meng Jin, Mengqing Xiong, Ke Hu.

Background: The hypoxia and immune status of the lung adenocarcinoma (LUAD) microenvironment appear to have combined impacts on prognosis. Therefore, deriving a prognostic signature by integrating hypoxia- and immune infiltrating cell-related genes (H&IICRGs) may add value over prognostic indices derived from genes driving either process alone.
Methods: Differentially expressed H&IICRGs (DE-H&IICRGs) were identified in The Cancer Genome Atlas transcriptomic data using limma, CIBERSORT, weighted gene co-expression network analysis, and intersection analysis. A stepwise Cox regression model was constructed to identify prognostic genes and to produce a gene signature based on DE-H&IICRGs. The potential biological functions associated with the gene signature were explored using functional enrichment analysis. The prognostic signature was externally validated in a separate cohort from the Gene Expression Omnibus database.
Results: Five prognostic genes associated with overall survival in LUAD were used in the DE-H&IICRG-based prognostic signature. Patients in the high-risk group had an inferior prognosis, which was validated in an independent external cohort, and had lower expression of most immune checkpoint genes. In multivariate analysis, only risk score and T stage were independent prognostic factors. Differentially expressed genes (DEGs) associated with the risk score were enriched for pathways related to cell cycle, hypoxia regulation, and immune response. TIDE analyses showed that low-risk LUAD patients might also respond better to immunotherapy.
Conclusion: This study establishes and validates a prognostic profile for LUAD patients that combines hypoxia and immune infiltrating cell-related genes. This signature may have clinical application both for prognostication and guiding individualized immunotherapy.

Keywords: LUAD; hypoxia; immune status; immunotherapy; lung adenocarcinoma; prognosis

DOI: https://doi.org/10.2147/IJGM.S342107