bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2019‒09‒08
three papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Mol Med Rep. 2019 Aug 26.
    Li B, Zhang J, Su Y, Hou Y, Wang Z, Zhao L, Sun S, Fu H.
      Lung cancer is one of the leading causes of tumor‑associated mortality, and >75% of patients with lung cancer have non‑small cell lung cancer (NSCLC). Pemetrexed, a folate antagonist, is a first‑line chemotherapy drug for NSCLC that is administered alone or in combination with cisplatin. The present study established in vitro cell models of PTEN inhibition and overexpression, and the effects of the treatment with pemetrexed were investigated in these cell models. Result from the present study demonstrated that treatment with pemetrexed suppressed lung cancer cell proliferation, inhibited mRNA and protein expression levels of anti‑apoptotic Bcl2, and increased the mRNA and the protein expression levels of pro‑apoptotic p53 and apoptosis regulator BAX. The present study suggested that pemetrexed regulated apoptosis via the inhibition of the mTOR/PI3K/AKT signaling pathway. Additionally, cellular processes associated with the aerobic oxidation of carbohydrates were identified to be significantly inhibited. The present findings suggested that treatment with pemetrexed may exhibit synergistic effects with PTEN on lung cancer cells via the inhibition of the PI3K/AKT/mTOR signaling pathway and through carbohydrate metabolism, and treatment with pemetrexed combined with PTEN overexpression may represent a novel therapeutic strategy for the treatment of NSCLC.
    DOI:  https://doi.org/10.3892/mmr.2019.10617
  2. Biochim Biophys Acta Mol Cell Res. 2019 Sep 03. pii: S0167-4889(19)30161-2. [Epub ahead of print] 118550
    Chang HL, Lin JC.
      Alternative splicing (AS) constitutes a pivotal mechanism for expanding the transcriptome and proteome diversity in higher eukaryotes. In contrast, misregulated AS events are relevant to carcinogenic signatures, including migration, angiogenesis, immortality, and drug resistance of cancer cells. Using a transcriptome analysis, discriminative splicing profiles of hypoxia-inducible factor (HIF)-1α transcripts were identified in tumorous tissues compared to adjacent normal tissues of lung cancer (LC) patients. In cancerous tissues or LC-derived cells, relatively high levels of HIF-1α-ex14 transcripts encoding the HIF-1αS isoform were noted compared to adjacent normal tissues and non-cancerous cells. The HIF-1αS isoform exhibited a more-prominent effect than that of the HIF-1αL isoform translated from HIF-1α+ex14 transcripts on enhancing promoter activities of the vascular endothelial growth factor receptor 2 (VEGFR2), serine/arginine splicing factor 1 (SRSF1), and c13orf25 genes. An increase in the SRSF1 protein facilitated the generation of HIF-1α-ex14 transcripts, whereas overexpression of RNA-binding motif protein 4 (RBM4) enhanced the expression of HIF-1α+ex14 transcripts in the A549 cells. Results of splicing reporter assays demonstrated the differential impacts of RBM4 and SRSF1 on the utilization of HIF-1α exon 14 in a CU element-dependent manner. In addition to transcriptional regulation, overexpression of the HIF-1αS and HIF-1αL isoforms differentially enhanced the metastatic signatures of A549 cells. Taken together, SRSF1 and RBM4 constitute an antagonistic mechanism on regulating the splicing profiles of HIF-1α gene, which is relevant to the oncogenic signatures of LC cells.
    Keywords:  A549; Alternative splicing; HIF-1α; RBM4; SRSF1
    DOI:  https://doi.org/10.1016/j.bbamcr.2019.118550
  3. J Hematol Oncol. 2019 Sep 05. 12(1): 91
    Hua Q, Jin M, Mi B, Xu F, Li T, Zhao L, Liu J, Huang G.
      BACKGROUND: Long non-coding RNAs (lncRNAs) have been associated with non-small cell lung cancer (NSCLC), but the underlying molecular mechanisms of their specific roles in mediating aerobic glycolysis have been poorly explored.METHODS: Next-generation RNA sequencing assay was performed to identify the differentially expressed RNAs between NSCLC tissues with high 18F-fluorodeoxyglucose (FDG) uptake and their adjacent normal lung tissues. LINC01123 expression in NSCLC tissues was measured by real-time PCR and in situ hybridization (ISH) assay. The biological role of LINC01123 in cell growth and aerobic glycolysis capability was determined by performing functional experiments in vitro and in vivo. Further, the transcription of LINC01123 was explored by bioinformatics analysis, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay. RNA immunoprecipitation (RIP) and luciferase analyses were used to confirm the predicted competitive endogenous RNA (ceRNA) mechanisms between LINC01123 and c-Myc.
    RESULTS: Three hundred sixty-four differentially expressed genes were identified in RNA-seq assay, and LINC01123 was one of the most overexpressed lncRNAs. Further validation in expanded NSCLC cohorts confirmed that LINC01123 was upregulated in 92 paired NSCLC tissues and associated with poor survival. Functional assays showed that LINC01123 promoted NSCLC cell proliferation and aerobic glycolysis. Mechanistic investigations revealed that LINC01123 was a direct transcriptional target of c-Myc. Meanwhile, LINC01123 increased c-Myc mRNA expression by sponging miR-199a-5p. In addition, rescue experiments showed that LINC01123 functioned as an oncogene depending on miR-199a-5p and c-Myc.
    CONCLUSION: Since LINC01123 is upregulated in NSCLC, correlates with prognosis, and controls proliferation and aerobic glycolysis by a positive feedback loop with c-Myc, it is expected to be a potential biomarker and therapeutic target for NSCLC.
    Keywords:  LINC01123; Long non-coding RNAs; aerobic glycolysis; c-Myc; non-small cell lung cancer
    DOI:  https://doi.org/10.1186/s13045-019-0773-y