bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2020‒08‒23
four papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Oncol Lett. 2020 Oct;20(4): 9
    Du H, Chen L, Luo F, Chen X, Li Y, Cheng Q.
      Beclin-1 and Bcl-2 expression abnormalities have been confirmed in different types of cancer. As important regulators of autophagy and apoptosis, respectively, these molecules serve a complex role in tumorigenesis. However, limited information is currently available regarding the association between Beclin-1 and Bcl-2 in (NSCLC). In the present study, the expression levels of Beclin-1 and Bcl-2 were detected in lung cancer tissues, and their prognostic significance was analyzed for NSCLC. A total of 120 patients with lung cancer who underwent surgical resection were included in the present study. Beclin-1 and Bcl-2 expression was assessed using immunohistochemistry and their associations with the overall survival (OS) in patients with NSCLC was examined. The expression rate of Beclin-1 was significantly lower in NSCLC tissues compared with that in adjacent tissues, whereas the expression rate of Bcl-2 was significantly higher in lung cancer tissues compared with that in adjacent tissues. Additionally, Beclin-1 and Bcl-2 protein expression was strongly associated (P<0.05) in NSCLC. Patients with NSCLC with low Beclin-1 expression were in more advanced stages, with more lymph node metastasis and more poorly differentiated tumors. Similarly, patients with NSCLC with high Bcl-2 expression were also in a more advanced stage and had more lymph node metastasis. Cox regression analysis revealed that the association between Bcl-2 expression and survival was not significant, while a multivariate analysis revealed that Beclin-1 expression was significantly associated with OS. Notably, Beclin-1 expression was significantly associated with OS only in patients with high Bcl-2 expression. In conclusion, the present data indicated that the autophagy activity is decreased in NSCLC. Beclin-1 expression was downregulated, while Bcl-2 expression was upregulated in NSCLC tissues compared with that in adjacent tissues. Additionally, these two proteins were associated with the occurrence and progression of NSCLC. Beclin-1 may be a promising prognostic marker for patients with NSCLC with high Bcl-2 expression. The present findings provided a more accurate prognostic assessment for patients with NSCLC. Furthermore, they may be used to actively follow-up and promptly treat patients with a poor prognosis, which may benefit a greater number of patients with NSCLC.
    Keywords:  Bcl-2; Beclin-1; autophagy; non-small cell lung cancer; prognosis
  2. Mol Cancer Res. 2020 Aug 14. pii: molcanres.0262.2020. [Epub ahead of print]
    Kim LC, Rhee CH, Chen J.
      Non-small cell lung cancer (NSCLC) is characterized by genomic alterations, yet a targetable mutation has not been discovered in nearly half of all patients. Recent studies have identified amplification of RICTOR, an mTORC2-specific cofactor, as a novel actionable target in NSCLC. mTORC2 is one of two distinct mTOR complexes to sense environmental cues and regulate a variety of cellular processes including cell growth, proliferation, and metabolism, all of which promote tumorigenesis when aberrantly regulated. Interestingly, other components of mTORC2 are not co-amplified with RICTOR in human lung cancer, raising the question as to whether RICTOR amplification-induced changes are dependent on mTORC2 function. To model RICTOR amplification, we overexpressed Rictor using the Cas9 Synergistic Activator system. Overexpression of Rictor increased mTORC2 integrity and signaling, but at the expense of mTORC1, suggesting that overexpressed Rictor recruits common components away from mTORC1. Additionally, Rictor overexpression increases proliferation and growth of NSCLC 3D cultures and tumors in vivo. Conversely, knockout of RICTOR leads to decreased mTORC2 formation and activity, but increased mTORC1 function. Because Rictor has mTOR-dependent and independent functions, we also knocked out mLST8, a shared mTOR co-factor but is specifically required for mTORC2 function. Inducible loss of mLST8 in RICTOR-amplified NSCLC cells inhibited mTORC2 integrity and signaling, tumor cell proliferation, and tumor growth. Collectively, these data identify a mechanism for Rictor-driven tumor progression and provide further rationale for development of an mTORC2-specific inhibitor. Implications: RICTOR amplification drives NSCLC proliferation through formation of mTORC2, suggesting mTORC2-specific inhibition could be a beneficial therapeutic option.
  3. Onco Targets Ther. 2020 ;13 7111-7123
    Yin D, Hua L, Wang J, Liu Y, Li X.
      Purpose: Long non-coding RNAs (lncRNAs) were confirmed to play important roles in human cancers. In this study, we explored the functional role of lncRNA double homeobox A pseudogene 8 (DUXAP8) in non-small-cell lung cancer (NSCLC).Methods: Real-time quantitative PCR (RT-qPCR) was used to detect DUXAP8 and microRNA-409-3p (miR-409-3p) expression. CCK-8, cell colony formation assay, and Transwell migration assay were performed to measure cell growth and migration, respectively. The expression of the relative proteins was detected by Western blot. Cell glycolysis was determined by glucose uptake, adenosine triphosphate (ATP) concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. Bioinformatics analysis and dual-luciferase reporter assay were used to measure the interaction among DUXAP8, miR-409-3p, hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). In vivo, subcutaneous tumor formation assay was performed in the nude mice.
    Results: DUXAP8 was highly expressed in NSCLC, while miR-409-3p was downregulated. High expression of DUXAP8 was positively related to the grade division and negatively associated with the 5-year survival rate of NSCLC patients. Downregulated DUXAP8 significantly suppressed cell growth, metastasis and glycolysis. Besides, DUXAP8 sponged miR-409-3p to promote HK2 and LDHA expression. DUXAP8 promoted cell viability, migration and glycolysis by regulating miR-409-3p/HK2/LDHA axis. Moreover, DUXAP8 downregulation markedly inhibited tumor growth in vivo.
    Conclusion: Our findings demonstrated that DUXAP8 served as an oncogene in the progression of NSCLC.
    Keywords:  DUXAP8; HK2; LDHA; miR-409-3p; non-small-cell lung cancer
  4. Ann Clin Lab Sci. 2020 Jul;50(4): 481-489
    Du H, Liu Y, Yuan Y, Zhang Y, Geng H.
      Glucose is the major source of energy for cells. Facilitative glucose transporters (GLUTs) mediate the transport of glucose into cells. The GLUT family has 14 members that are expressed in different tissues of the body and play essential roles in sustaining the energy demand. However, the prognostic value of the majority of GLUTs in lung cancer remains elusive and should be further evaluated in clinical studies. Thus, we investigated the prognostic data of GLUTs in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients through the "Kaplan-Meier (KM) plotter" database. In the current study, we found that 12 members of the GLUTs family were significantly associated with prognosis of LUAD patients, but GLUT8 was not. High expression levels of GLUT10, GLUT12, and GLUT13 were significantly associated with better overall survival (OS) in LUAD, while the other 9 members were associated with worse OS. However, GLUT family members were not correlated with OS in LUSC, although high mRNA expression level of GLUT1 tend to show an inferior OS (P=0.057). The prognostic value of GLUTs according to smoking status was also assessed. In conclusion, our study provides new insights into the prognostic values of GLUT members in LUAD, but the molecular mechanisms by which GLUTs contribute to disease aggression and the different functional roles of GLUT members need further study.
    Keywords:  KM plotter; NSCLC; glucose transporters; prognosis