Expression and potential mechanism of metabolism-related genes and CRLS1 in non-small cell lung cancer

Feng,Hai‑Ming; Zhao,Ye; Zhang,Jian‑Ping; Zhang,Jian‑Hua; Jiang,Peng; Li,Bin; Wang,Cheng

doi:10.3892/ol.2017.7591

Expression and potential mechanism of metabolism-related genes and CRLS1 in non-small cell lung cancer

Authors:
- Hai‑Ming Feng
- Ye Zhao
- Jian‑Ping Zhang
- Jian‑Hua Zhang
- Peng Jiang
- Bin Li
- Cheng Wang
View Affiliations

Affiliations: Department of Thoracic Surgery, The Second Affiliated Hospital of Lanzhou University, Lanzhou, Gansu 730030, P.R. China, The Evidence Based Medicine Center of Lanzhou University, Lanzhou, Gansu 730000, P.R. China, Department of Neurosurgery, The Second Affiliated Hospital of Lanzhou University, Lanzhou, Gansu 730030, P.R. China, Department of Thoracic Surgery, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong 518100, P.R. China
Published online on: December 12, 2017 https://doi.org/10.3892/ol.2017.7591
Pages: 2661-2668

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cardiolipin (CL) is a phospholipid localized in the mitochondria, which is essential for mitochondrial structure and function. Human cardiolipin synthase 1 (CRLS1) is important in regulating phosphatidylglycerol (PG) remodeling and CL biosynthesis. However, the expression and distinct prognostic value of CRLS1 in neoplasms, including non‑small cell lung cancer (NSCLC), is not well established. In the present study, the mRNA expression of CRLS1 was investigated using Oncomine analysis and the prognostic value was assessed using the Kaplan‑Meier plotter database for patients with NSCLC. The results of the analyses indicated that the expression of CRLS1 in lung cancer was lower, compared with that in normal lung tissues. Notably, a high expression of CRLS1 was found to be associated with improved overall survival (OS) in all patients with NSCLC and lung adenocarcinoma (Ade). However, this was not observed in patients with squamous cell carcinoma (SCC). The results also demonstrated an association between the mRNA expression of CRLS1 and the clinicopathological parameters of patients with NSCLC, including sex, smoking status, tumor grade, clinical stage, lymph node status and chemotherapy. These results indicated that CRLS1 was associated with improved prognosis in patients with NSCLC, particularly at an early stage (T1N1M0). In addition, it was revealed that CRLS1 was co‑expressed with well‑known genes associated with metabolism using Gene Ontology term enrichment analysis. Kyoto Encyclopedia of Genes and Genomes pathway analysis also showed that tumor‑related metabolism and the mitogen‑activated protein kinase (MAPK) signaling pathways were enriched with CRLS1‑co‑expression genes. The results of the present study suggested that CRLS1 may be a novel tumor suppressor involved in regulating lipid and seleno‑amino acid metabolism in the tumor microenvironment, and suppressing the MAPK signaling pathway during tumorigenesis and development. Comprehensive evaluation of the expression, prognosis and potential mechanism of CRLS1 is likely to promote an improved understanding of the complexity of the molecular biology of NSCLC.

View Figures

View References

1	van der Knaap JA and Verrijzer CP: Undercover: Gene control by metabolites and metabolic enzymes. Genes Dev. 30:2345–2369. 2016. View Article : Google Scholar : PubMed/NCBI
2	Saadi H, Seillier M and Carrier A: The stress protein TP53INP1 plays a tumor suppressive role by regulating metabolic homeostasis. Biochimie. 118:44–50. 2015. View Article : Google Scholar : PubMed/NCBI
3	Hostetler K: Chapter 6 polyglycerophospholipids: Phosphatidylglycerol, diphosphatidylglycerol and bis, (monoacylglycero) phosphate. New Compr Biochem. 4:215–261. 1982. View Article : Google Scholar
4	Hatch GM: Cell biology of cardiac mitochondrial phospholipids. Biochem Cell Biol. 82:99–112. 2004. View Article : Google Scholar : PubMed/NCBI
5	Zhang M, Mileykovskaya E and Dowhan W: Gluing the respiratory chain together. Cardiolipin is required for supercomplex formation in the inner mitochondrial membrane. J Biol Chem. 277:43553–43556. 2002. View Article : Google Scholar : PubMed/NCBI
6	Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C and Kroemer G: Mechanisms of cytochrome C release from mitochondria. Cell Death Differ. 13:1423–1433. 2006. View Article : Google Scholar : PubMed/NCBI
7	Ott M, Zhivotovsky B and Orrenius S: Role of cardiolipin in cytochrome c release from mitochondria. Cell Death Differ. 14:1243–1247. 2007. View Article : Google Scholar : PubMed/NCBI
8	Hostetler KY, Van den Bosch H and Van Deenen LL: Biosynthesis of cardiolipin in liver mitochondria. Biochim Biophys Acta. 239:113–119. 1971. View Article : Google Scholar : PubMed/NCBI
9	Lu B, Xu FY, Jiang YJ, Choy PC, Hatch GM, Grunfeld C and Feingold KR: Cloning and characterization of a cDNA encoding human cardiolipin synthase (hCLS1). J Lipid Res. 47:1140–1145. 2006. View Article : Google Scholar : PubMed/NCBI
10	Houtkooper RH, Akbari H, van Lenthe H, Kulik W, Wanders RJ, Frentzen M and Vaz FM: Identification and characterization of human cardiolipin synthase. FEBS Lett. 580:3059–3064. 2006. View Article : Google Scholar : PubMed/NCBI
11	Abdollahi A and Omranipour R: Is increase of homocysteine, anti-cardiolipin, anti-phospholipid antibodies associated with breast tumors? Acta Med Iran. 53:681–685. 2015.PubMed/NCBI
12	Schvartsman G, Ferrarotto R and Massarelli E: Checkpoint inhibitors in lung cancer: Latest developments and clinical potential. Ther Adv Med Oncol. 8:460–473. 2016. View Article : Google Scholar : PubMed/NCBI
13	Santarpia M, Giovannetti E, Rolfo C, Karachaliou N, González-Cao M, Altavilla G and Rosell R: Recent developments in the use of immunotherapy in non-small cell lung cancer. Expert Rev Respir Med. 10:781–798. 2016. View Article : Google Scholar : PubMed/NCBI
14	Cufer T, Ovcaricek T and O'Brien ME: Systemic therapy of advanced non-small cell lung cancer: Major-developments of the last 5-years. Eur J Cancer. 49:1216–1225. 2013. View Article : Google Scholar : PubMed/NCBI
15	Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated Data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI
16	Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C, Kulkarni P, et al: Oncomine 3.0: Genes, pathways and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 9:166–180. 2007. View Article : Google Scholar : PubMed/NCBI
17	Gyorffy B, Surowiak P, Budczies J and Lánczky A: Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One. 8:e822412013. View Article : Google Scholar : PubMed/NCBI
18	Huang da W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
19	Huang da W, Sherman BT and Lempicki RA: Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37:1–13. 2009. View Article : Google Scholar : PubMed/NCBI
20	Shirlaw JT: The metabolism of tumors. Br Med J. 1:741931. View Article : Google Scholar
21	Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI
22	Veech RL: The therapeutic implications of ketone bodies: The effects of ketone bodies in pathological conditions: Ketosis, ketogenic diet, redox states, insulin resistance and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids. 70:309–319. 2004. View Article : Google Scholar : PubMed/NCBI
23	Seyfried TN and Mukherjee P: Targeting energy metabolism in brain cancer: Review and hypothesis. Nutr Metab. 2:302005. View Article : Google Scholar
24	Wu M, Neilson A, Swift AL, Moran R, Tamagnine J, Parslow D, Armistead S, Lemire K, Orrell J, Teich J, et al: Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am J Physiol Cell Physiol. 292:C125–C136. 2007. View Article : Google Scholar : PubMed/NCBI
25	Galarraga J, Loreck DJ, Graham JF, DeLaPaz RL, Smith BH, Hallgren D and Cummins CJ: Glucose metabolism in human gliomas: Correspondence of in situ and in vitro metabolic rates and altered energy metabolism. Metab Brain Dis. 1:279–291. 1986. View Article : Google Scholar : PubMed/NCBI
26	Baggetto LG, Clottes E and Vial C: Low mitochondrial proton leak due to high membrane cholesterol content and cytosolic creatine kinase as two features of the deviant bioenergetics of Ehrlich and AS30-D tumor cells. Cancer Res. 52:4935–4941. 1992.PubMed/NCBI
27	Bergelson LD, Dyatlovitskaya EV, Sorokina IB and Gorkova NP: Phospholipid compositon of mitochondria and microsomes from regenerating rat liver and hepatomas of different growth rate. Biochim Biophys Acta. 360:361–365. 1974. View Article : Google Scholar : PubMed/NCBI
28	Chicco AJ and Sparagna GC: Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol. 292:C33–C44. 2007. View Article : Google Scholar : PubMed/NCBI
29	Hoch FL: Cardiolipins and biomembrane function. Biochim Biophys Acta. 1113:71–133. 1992. View Article : Google Scholar : PubMed/NCBI
30	Kiebish MA, Han X, Cheng H, Chuang JH and Seyfried TN: Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: Lipidomic evidence supporting the Warburg theory of cancer. J Lipid Res. 49:2545–2556. 2008. View Article : Google Scholar : PubMed/NCBI
31	Hardy S, El-Assaad W, Przybytkowski E, Joly E, Prentki M and Langelier Y: Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin. J Biol Chem. 278:31861–31870. 2003. View Article : Google Scholar : PubMed/NCBI
32	Mcmillin JB and Dowhan W: Cardiolipin and apoptosis. Biochim Biophys Acta. 1585:97–107. 2002. View Article : Google Scholar : PubMed/NCBI
33	Kim EK and Choi EJ: Compromised MAPK signaling in human diseases: An update. Arch Toxicol. 89:867–882. 2015. View Article : Google Scholar : PubMed/NCBI
34	Kim EK and Choi EJ: Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802:396–405. 2010. View Article : Google Scholar : PubMed/NCBI
35	Zhang B, Zhou Z, Lin H, Lv X, Fu J, Lin P, Zhu C and Wang H: Protein phosphatase 1A (PPM1A) is involved in human cytotrophoblast cell invasion and migration. Histochem Cell Biol. 132:169–179. 2009. View Article : Google Scholar : PubMed/NCBI
36	Li R, Gong Z, Pan C, Xie DD, Tang JY, Cui M, Xu YF, Yao W, Pang Q, Xu ZG, et al: Metal-dependent protein phosphatase 1A functions as an extracellular signal-regulated kinase phosphatase. FEBS J. 280:2700–2711. 2013. View Article : Google Scholar : PubMed/NCBI
37	Su PH, Lin YW, Huang RL, Liao YP, Lee HY, Wang HC, Chao TK, Chen CK, Chan MW, Chu TY, et al: Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and serves as a biomarker of invasive cervical cancer. Oncogene. 32:15–26. 2013. View Article : Google Scholar : PubMed/NCBI
38	Blanco-Aparicio C, Torres J and Pulido R: A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase. J Cell Biol. 147:1129–1136. 1999. View Article : Google Scholar : PubMed/NCBI
39	Bhalla US, Ram PT and Iyengar R: MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science. 297:1018–1023. 2002. View Article : Google Scholar : PubMed/NCBI
40	Bermudez O, Pagès G and Gimond C: The dual-specificity MAP kinase phosphatases: Critical roles in development and cancer. Am J Physiol Cell Physiol. 299:C189–C202. 2010. View Article : Google Scholar : PubMed/NCBI
41	Caunt CJ and Keyse SM: Dual-specificity MAP kinase phosphatases (MKPs): Shaping the outcome of MAP kinase signalling. FEBS J. 280:489–504. 2013. View Article : Google Scholar : PubMed/NCBI
42	Ham JE, Oh EK, Kim DH and Choi SH: Differential expression profiles and roles of inducible DUSPs and ERK1/2-specific constitutive DUSP6 and DUSP7 in microglia. Biochem Biophys Res Commun. 467:254–260. 2015. View Article : Google Scholar : PubMed/NCBI
43	Huo Y, Rangarajan P, Ling EA and Dheen ST: Dexamethasone inhibits the Nox-dependent ROS production via suppression of MKP-1-dependent MAPK pathways in activated microglia. BMC Neurosci. 12:492011. View Article : Google Scholar : PubMed/NCBI
44	Zeke A, Misheva M, Reményi A and Bogoyevitch MA: JNK signaling: Regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev. 80:793–835. 2016. View Article : Google Scholar : PubMed/NCBI
45	Segalés J, Perdiguero E and Muñoz-Cánoves P: Regulation of muscle stem cell functions: A focus on the p38 MAPK signaling pathway. Front Cell Dev Biol. 4:912016. View Article : Google Scholar : PubMed/NCBI
46	Chang L and Karin M: Mammalian MAP kinase signalling cascades. Nature. 410:37–40. 2001. View Article : Google Scholar : PubMed/NCBI
47	Schrauzer GN, White DA and Schnieder CJ: Cancer mortality correlation studies-III: Statistical associations with dietary selenium intakes. Bioinorg Chem. 7:23–31. 1997. View Article : Google Scholar
48	Willis MS and Wians FH: The role of nutrition in preventing prostate cancer: A review of the proposed mechanism of action of various dietary substances. Clin Chim Acta. 330:57–83. 2003. View Article : Google Scholar : PubMed/NCBI
49	Nyman DW, Stratton M Suzanne, Kopplin MJ, Dalkin BL, Nagle RB and Jay Gandolfi A: Selenium and selenomethionine levels in prostate cancer patients. Cancer Detect Prev. 28:8–16. 2004. View Article : Google Scholar : PubMed/NCBI
50	Morey M, Corominas M and Serras F: DIAP1 suppresses ROS-induced apoptosis caused by impairment of the selD/sps1 homolog in Drosophila. J Cell Sci. 116:4597–4604. 2003. View Article : Google Scholar : PubMed/NCBI
51	Chung HJ, Yoon SI, Shin SH, Koh YA, Lee SJ, Lee YS and Bae S: p53-Mediated enhancement of radiosensitivity by selenophosphate synthetase 1 overexpression. J Cell Physiol. 209:131–141. 2006. View Article : Google Scholar : PubMed/NCBI