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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

The Potential of Lipid Droplet-associated Genes as Diagnostic and Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma

Author(s): Yu-Ting Bai, Xin Wang, Ming-Jing He, Ji-Rong Xie, Xiao-Jie Chen and Gang Zhou*

Volume 27, Issue 1, 2024

Published on: 19 May, 2023

Page: [136 - 147] Pages: 12

DOI: 10.2174/1386207326666230328123223

Price: $65

Abstract

Abstract: Objective: The role of lipid droplets (LDs) and lipid droplet-associated genes (LD-AGs) remains unclear in head and neck squamous cell carcinoma (HNSCC). This study aimed to investigate LDs in HNSCC and identify LD-AGs essential for the diagnosis and prognosis of HNSCC patients.

Methods: The LDs in the HNSCC and normal cell lines were stained with oil red O. Bioinformatic analysis was used to find LD-AGs in HNSCC that had diagnostic and prognostic significance.

Results: LDs accumulation was increased in HNSCC cell lines compared with normal cell lines (P<0.05). Fifty-three differentially expressed genes, including 34 upregulated and 19 downregulated, were found in HNSCC based on the TCGA platform (P<0.05). Then, 53 genes were proved to be functionally enriched in lipid metabolism and LDs. Among them, with an AUC value > 0.7, 34 genes demonstrated a high predictive power. Six genes (AUP1, CAV1, CAV2, CAVIN1, HILPDA, and SQLE) out of 34 diagnostic genes were linked to overall survival in patients with HNSCC (P<0.05). The significant prognostic factors AUP1, CAV1, CAV2, and SQLE were further identified using the univariate and multivariate cox proportional hazard models (P<0.05). The protein expression of CAV2 and SQLE was significantly increased in the HNSCC tissue compared to normal tissues (P<0.05). Finally, the knockdown of the four LD-AGs decreased LDs accumulation, respectively.

Conclusions: Increased LDs accumulation was a hallmark of HNSCC, and AUP1, CAV1, CAV2, and SQLE were discovered as differentially expressed LD-AGs with diagnostic and prognostic potential in HNSCC.

Graphical Abstract

[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Wei, T.; Choi, S.; Buehler, D.; Anderson, R.A.; Lambert, P.F.A. PI3K/AKT Scaffolding Protein, IQ Motif–Containing GTPase Associating Protein 1 (IQGAP1), promotes head and neck carcinogenesis. Clin. Cancer Res., 2020, 26(1), 301-311.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-1063] [PMID: 31597661]
[3]
Chen, X.; Mims, J.; Huang, X.; Singh, N.; Motea, E.; Planchon, S.M.; Beg, M.; Tsang, A.W.; Porosnicu, M.; Kemp, M.L.; Boothman, D.A.; Furdui, C.M. Modulators of redox metabolism in head and neck cancer. Antioxid. Redox Signal., 2018, 29(16), 1660-1690.
[http://dx.doi.org/10.1089/ars.2017.7423] [PMID: 29113454]
[4]
Magtanong, L.; Ko, P.J.; Dixon, S.J. Emerging roles for lipids in non-apoptotic cell death. Cell Death Differ., 2016, 23(7), 1099-1109.
[http://dx.doi.org/10.1038/cdd.2016.25] [PMID: 26967968]
[5]
Lee, P.; Chandel, N.S.; Simon, M.C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol., 2020, 21(5), 268-283.
[http://dx.doi.org/10.1038/s41580-020-0227-y] [PMID: 32144406]
[6]
Pennetta, G.; Welte, M.A. Emerging links between lipid droplets and motor neuron diseases. Dev. Cell, 2018, 45(4), 427-432.
[http://dx.doi.org/10.1016/j.devcel.2018.05.002] [PMID: 29787708]
[7]
Cotte, A.K.; Aires, V.; Fredon, M.; Limagne, E.; Derangère, V.; Thibaudin, M.; Humblin, E.; Scagliarini, A.; de Barros, J.P.P.; Hillon, P.; Ghiringhelli, F.; Delmas, D. Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance. Nat. Commun., 2018, 9(1), 322.
[http://dx.doi.org/10.1038/s41467-017-02732-5] [PMID: 29358673]
[8]
Li, Z.; Liu, H.; Luo, X. Lipid droplet and its implication in cancer progression. Am. J. Cancer Res., 2020, 10(12), 4112-4122.
[PMID: 33414989]
[9]
de la Rosa Rodriguez, M.A.; Deng, L.; Gemmink, A.; van Weeghel, M.; Aoun, M.L.; Warnecke, C.; Singh, R.; Borst, J.W.; Kersten, S. Hypoxia-inducible lipid droplet-associated induces DGAT1 and promotes lipid storage in hepatocytes. Mol. Metab., 2021, 47, 101168.
[http://dx.doi.org/10.1016/j.molmet.2021.101168] [PMID: 33465519]
[10]
He, Y.; Dong, Y.; Zhang, X.; Ding, Z.; Song, Y.; Huang, X.; Chen, S.; Wang, Z.; Ni, Y.; Ding, L. Lipid droplet-related PLIN2 in CD68+ tumor-associated macrophage of oral squamous cell carcinoma: Implications for cancer prognosis and immunotherapy. Front. Oncol., 2022, 12, 824235.
[http://dx.doi.org/10.3389/fonc.2022.824235] [PMID: 35372038]
[11]
Bai, R.; Rebelo, A.; Kleeff, J.; Sunami, Y. Identification of prognostic lipid droplet-associated genes in pancreatic cancer patients via bioinformatics analysis. Lipids Health Dis., 2021, 20(1), 58.
[http://dx.doi.org/10.1186/s12944-021-01476-y] [PMID: 34078402]
[12]
Mi, H.; Muruganujan, A.; Ebert, D.; Huang, X.; Thomas, P.D. PANTHER version 14: More genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res., 2019, 47(D1), D419-D426.
[http://dx.doi.org/10.1093/nar/gky1038] [PMID: 30407594]
[13]
Pontén, F.; Jirström, K.; Uhlen, M. The Human Protein Atlas—a tool for pathology. J. Pathol., 2008, 216(4), 387-393.
[http://dx.doi.org/10.1002/path.2440] [PMID: 18853439]
[14]
Mejhert, N.; Gabriel, K.R.; Frendo-Cumbo, S.; Krahmer, N.; Song, J.; Kuruvilla, L.; Chitraju, C.; Boland, S.; Jang, D.K.; von Grotthuss, M.; Costanzo, M.C.; Rydén, M.; Olzmann, J.A.; Flannick, J.; Burtt, N.P.; Farese, R.V., Jr; Walther, T.C. The lipid droplet knowledge portal: A resource for systematic analyses of lipid droplet biology. Dev. Cell, 2022, 57(3), 387-397.e4.
[http://dx.doi.org/10.1016/j.devcel.2022.01.003] [PMID: 35134345]
[15]
Mejhert, N.; Kuruvilla, L.; Gabriel, K.R.; Elliott, S.D.; Guie, M.A.; Wang, H.; Lai, Z.W.; Lane, E.A.; Christiano, R.; Danial, N.N.; Farese, R.V., Jr; Walther, T.C. Partitioning of MLX-family transcription factors to lipid droplets regulates metabolic gene expression. Mol. Cell, 2020, 77(6), 1251-1264.e9.
[http://dx.doi.org/10.1016/j.molcel.2020.01.014] [PMID: 32023484]
[16]
Smith, C.E.; Tsai, Y.C.; Liang, Y.H.; Khago, D.; Mariano, J.; Li, J.; Tarasov, S.G.; Gergel, E.; Tsai, B.; Villaneuva, M.; Clapp, M.E.; Magidson, V.; Chari, R.; Byrd, R.A.; Ji, X.; Weissman, A.M. A structurally conserved site in AUP1 binds the E2 enzyme UBE2G2 and is essential for ER-associated degradation. PLoS Biol., 2021, 19(12), e3001474.
[http://dx.doi.org/10.1371/journal.pbio.3001474] [PMID: 34879065]
[17]
Jo, Y.; Hartman, I.Z.; DeBose-Boyd, R.A. Ancient ubiquitous protein-1 mediates sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl CoA reductase in lipid droplet–associated endoplasmic reticulum membranes. Mol. Biol. Cell, 2013, 24(3), 169-183.
[http://dx.doi.org/10.1091/mbc.e12-07-0564] [PMID: 23223569]
[18]
Chen, C.; Zhao, W.; Lu, X.; Ma, Y.; Zhang, P.; Wang, Z.; Cui, Z.; Xia, Q. AUP1 regulates lipid metabolism and induces lipid accumulation to accelerate the progression of renal clear cell carcinoma. Cancer Sci., 2022, 113(8), 2600-2615.
[http://dx.doi.org/10.1111/cas.15445] [PMID: 35633317]
[19]
Blouin, C.M.; Le Lay, S.; Eberl, A.; Köfeler, H.C.; Guerrera, I.C.; Klein, C.; Le Liepvre, X.; Lasnier, F.; Bourron, O.; Gautier, J.F.; Ferré, P.; Hajduch, E.; Dugail, I. Lipid droplet analysis in caveolin-deficient adipocytes: Alterations in surface phospholipid composition and maturation defects. J. Lipid Res., 2010, 51(5), 945-956.
[http://dx.doi.org/10.1194/jlr.M001016] [PMID: 19965594]
[20]
Jiang, E.; Xu, Z.; Wang, M.; Yan, T.; Huang, C.; Zhou, X.; Liu, Q.; Wang, L.; Chen, Y.; Wang, H.; Liu, K.; Shao, Z.; Shang, Z. Tumoral microvesicle–activated glycometabolic reprogramming in fibroblasts promotes the progression of oral squamous cell carcinoma. FASEB J., 2019, 33(4), 5690-5703.
[http://dx.doi.org/10.1096/fj.201802226R] [PMID: 30698991]
[21]
Richter, A.; Fichtner, A.; Joost, J.; Brockmeyer, P.; Kauffmann, P.; Schliephake, H.; Hammerstein-Equord, A.; Kueffer, S.; Urlaub, H.; Oellerich, T.; Ströbel, P.; Bohnenberger, H.; Bremmer, F. Quantitative proteomics identifies biomarkers to distinguish pulmonary from head and neck squamous cell carcinomas by immunohistochemistry. J. Pathol. Clin. Res., 2022, 8(1), 33-47.
[http://dx.doi.org/10.1002/cjp2.244] [PMID: 34647699]
[22]
Kato, K.; Miyazawa, H.; Kobayashi, H.; Noguchi, N.; Lambert, D.; Kawashiri, S. Caveolin-1 expression at metastatic lymph nodes predicts unfavorable outcome in patients with oral squamous cell carcinoma. Pathol. Oncol. Res., 2020, 26(4), 2105-2113.
[http://dx.doi.org/10.1007/s12253-019-00791-1] [PMID: 31907776]
[23]
Scherer, P.E.; Lewis, R.Y.; Volonté, D.; Engelman, J.A.; Galbiati, F.; Couet, J.; Kohtz, D.S.; van Donselaar, E.; Peters, P.; Lisanti, M.P. Cell-type and tissue-specific expression of caveolin-2. Caveolins 1 and 2 co-localize and form a stable hetero-oligomeric complex in vivo. J. Biol. Chem., 1997, 272(46), 29337-29346.
[http://dx.doi.org/10.1074/jbc.272.46.29337] [PMID: 9361015]
[24]
Liu, Z.Q.; Ren, J.J.; Zhao, J.L.; Zang, J.; Long, Q.F.; Du, J.J.; Jia, X.T.; Gu, N.B.; Di, Z.L.; Qian, Y.H.; Li, S.Z. MicroRNA-144 represses gliomas progression and elevates susceptibility to Temozolomide by targeting CAV2 and FGF7. Sci. Rep., 2020, 10(1), 4155.
[http://dx.doi.org/10.1038/s41598-020-60218-9] [PMID: 32139705]
[25]
Fujimoto, T.; Kogo, H.; Ishiguro, K.; Tauchi, K.; Nomura, R. Caveolin-2 is targeted to lipid droplets, a new “membrane domain” in the cell. J. Cell Biol., 2001, 152(5), 1079-1086.
[http://dx.doi.org/10.1083/jcb.152.5.1079] [PMID: 11238462]
[26]
Zhu, Y.; Tian, J.; Peng, X.; Wang, X.; Yang, N.; Ying, P.; Wang, H.; Li, B.; Li, Y.; Zhang, M.; Cai, Y.; Lu, Z.; Niu, S.; Li, Y.; Zhong, R.; Chang, J.; Miao, X. A genetic variant conferred high expression of CAV2 promotes pancreatic cancer progression and associates with poor prognosis. Eur. J. Cancer, 2021, 151, 94-105.
[http://dx.doi.org/10.1016/j.ejca.2021.04.008] [PMID: 33975060]
[27]
Elsheikh, S.E.; Green, A.R.; Rakha, E.A.; Samaka, R.M.; Ammar, A.A.; Powe, D.; Reis-Filho, J.S.; Ellis, I.O. Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype. Br. J. Cancer, 2008, 99(2), 327-334.
[http://dx.doi.org/10.1038/sj.bjc.6604463] [PMID: 18612310]
[28]
Li, J.; Yang, T.; Wang, Q.; Li, Y.; Wu, H.; Zhang, M.; Qi, H.; Zhang, H.; Li, J. Upregulation of SQLE contributes to poor survival in head and neck squamous cell carcinoma. Int. J. Biol. Sci., 2022, 18(9), 3576-3591.
[http://dx.doi.org/10.7150/ijbs.68216] [PMID: 35813482]
[29]
Ta, M.T.; Kapterian, T.S.; Fei, W.; Du, X.; Brown, A.J.; Dawes, I.W.; Yang, H. Accumulation of squalene is associated with the clustering of lipid droplets. FEBS J., 2012, 279(22), 4231-4244.
[http://dx.doi.org/10.1111/febs.12015] [PMID: 23013491]
[30]
Jun, S.Y.; Brown, A.J.; Chua, N.K.; Yoon, J.Y.; Lee, J.J.; Yang, J.O.K.; Jang, I.; Jeon, S.J.; Choi, T.I.K.; Kim, C.H.; Kim, N.S. Reduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis. Gastroenterology, 2021, 160(4), 1194-1207.e28.
[http://dx.doi.org/10.1053/j.gastro.2020.09.009] [PMID: 32946903]

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