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Combinatorial Chemistry & High Throughput Screening

Author(s): Chengcheng Liao, Qian Wang, Jiaxing An, Hui Wang, Linlin Xiao, Qian Long, Hongbo Zhao, Jianguo Liu* and Xiaoyan Guan*

DOI: 10.2174/1386207325666220509191153

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FAM3 Family as Prognostic Factors for Head and Neck Squamous Cell Carcinoma

Page: [539 - 558] Pages: 20

  • * (Excluding Mailing and Handling)

Abstract

Background: Although head and neck squamous cell carcinoma (HNSCC) is a common malignancy, the molecular biology landscape underlying its occurrence and development remains poorly understood. The family with sequence similarity (FAM) 3 family of proteins includes four family members, namely FAM3A, FAM3B, FAM3C and FAM3D. In particular, FAM3C has been previously reported to be closely associated with various human malignancies.

Methods: Combining analyses using The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, Tumor Immune Estimation Resource and MethSurv databases, coupled with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes bioinformatics tools, the possible biological function and key pathways regulated by the FAM3 family in HNSCC were probed.

Results: High FAM3A expression was found to increase HNSCC mitochondrial biosynthesis and energy metabolism, inhibit immune cell infiltration in the HNSCC tumor microenvironment, and be associated with poor prognosis. By contrast, lower expression levels of FAM3B in HNSCC were associated with a poorer prognosis in patients with HNSCC. This was most likely due to the finding that FAM3B can inhibit the development of HNSCC by increasing immune cell infiltration, inhibiting epithelial-mesenchymal transition (EMT) and the cytochrome P450 pathway. FAM3C was overexpressed in oral squamous cell carcinoma (OSCC) and associated with increased OSCC cell stemness, immune escape and EMT. In the present study, FAM3C expression was associated with poor prognosis for patients with HNSCC by suppressing tumor immune cell infiltration. FAM3C expression was also positively correlated with the expression of epithelial and mesenchymal markers such as E-cadherin, N-cadherin, Vimentin and ZO-1, which may promote the partial EMT status in HNSCC and greatly increase its malignancy. FAM3D is a maintenance factor of the epithelial phenotype in HNSCC that can inhibit the progression of EMT, promote tumor immune cell infiltration and inhibit HNSCC progression. In addition, methylation levels of the FAM3 gene family were correlated with the overall survival rate of HNSCC.

Conclusion: The FAM3 family may be applied as a biomarker and potential therapeutic target for HNSCC.

Keywords: HNSCC, FAM3, EMT, tumor microenvironment, methylation, prognosis.

Graphical Abstract

[1]
Jiang, P.; Li, Y.; Xu, Z.; He, S. A signature of 17 immune-related gene pairs predicts prognosis and immune status in HNSCC patients. Transl. Oncol., 2021, 14(1), 100924.
[http://dx.doi.org/10.1016/j.tranon.2020.100924] [PMID: 33221687]
[2]
Marur, S.; Forastiere, A.A. Head and neck cancer: Changing epidemiology, diagnosis, and treatment. Mayo Clin. Proc., 2008, 83(4), 489-501.
[http://dx.doi.org/10.4065/83.4.489] [PMID: 18380996]
[3]
Liao, C.; An, J.; Tan, Z.; Xu, F.; Liu, J.; Wang, Q. Changes in protein glycosylation in head and neck squamous cell carcinoma. J. Cancer, 2021, 12(5), 1455-1466.
[http://dx.doi.org/10.7150/jca.51604] [PMID: 33531990]
[4]
Johnson, D.E.; Burtness, B.; Leemans, C.R.; Lui, V.W.Y.; Bauman, J.E.; Grandis, J.R. Head and neck squamous cell carcinoma. Nat. Rev. Dis. Primers, 2020, 6(1), 92.
[http://dx.doi.org/10.1038/s41572-020-00224-3] [PMID: 33243986]
[5]
Leemans, C.R.; Snijders, P.J.F.; Brakenhoff, R.H. The molecular landscape of head and neck cancer. Nat. Rev. Cancer, 2018, 18(5), 269-282.
[http://dx.doi.org/10.1038/nrc.2018.11] [PMID: 29497144]
[6]
Idel, C.; Ribbat-Idel, J.; Kuppler, P.; Krupar, R.; Offermann, A.; Vogel, W.; Rades, D.; Kirfel, J.; Wollenberg, B.; Perner, S. EVI1 as a marker for lymph node metastasis in HNSCC. Int. J. Mol. Sci., 2020, 21(3), 854.
[http://dx.doi.org/10.3390/ijms21030854] [PMID: 32013033]
[7]
Ervin, T.J.; Clark, J.R.; Weichselbaum, R.R.; Fallon, B.G.; Miller, D.; Fabian, R.L.; Posner, M.R.; Norris, C.M., Jr; Tuttle, S.A.; Schoenfeld, D.A. An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck. J. Clin. Oncol., 1987, 5(1), 10-20.
[http://dx.doi.org/10.1200/JCO.1987.5.1.10] [PMID: 2433406]
[8]
Chin, D.; Boyle, G.M.; Porceddu, S.; Theile, D.R.; Parsons, P.G.; Coman, W.B. Head and neck cancer: Past, present and future. Expert Rev. Anticancer Ther., 2006, 6(7), 1111-1118.
[http://dx.doi.org/10.1586/14737140.6.7.1111] [PMID: 16831082]
[9]
Bernier, J. A multidisciplinary approach to squamous cell carcinomas of the head and neck: An update. Curr. Opin. Oncol., 2008, 20(3), 249-255.
[http://dx.doi.org/10.1097/CCO.0b013e3282faa0b1] [PMID: 18391622]
[10]
Liao, C.; Wang, Q.; An, J.; Long, Q.; Wang, H.; Xiang, M.; Xiang, M.; Zhao, Y.; Liu, Y.; Liu, J.; Guan, X. Partial EMT in squamous cell carcinoma: A Snapshot. Int. J. Biol. Sci., 2021, 17(12), 3036-3047.
[http://dx.doi.org/10.7150/ijbs.61566] [PMID: 34421348]
[11]
Zhu, Y.; Xu, G.; Patel, A.; McLaughlin, M.M.; Silverman, C.; Knecht, K.; Sweitzer, S.; Li, X.; McDonnell, P.; Mirabile, R.; Zimmerman, D.; Boyce, R.; Tierney, L.A.; Hu, E.; Livi, G.P.; Wolf, B.; Abdel-Meguid, S.S.; Rose, G.D.; Aurora, R.; Hensley, P.; Briggs, M.; Young, P.R. Cloning, expression, and initial characterization of a novel cytokine-like gene family. Genomics, 2002, 80(2), 144-150.
[http://dx.doi.org/10.1006/geno.2002.6816] [PMID: 12160727]
[12]
Yang, J.; Guan, Y. Family with sequence similarity 3 gene family and nonalcoholic fatty liver disease. J. Gastroenterol. Hepatol., 2013, 28(Suppl. 1), 105-111.
[http://dx.doi.org/10.1111/jgh.12033] [PMID: 23855304]
[13]
Zhang, X.; Yang, W.; Wang, J.; Meng, Y.; Guan, Y.; Yang, J. FAM3 gene family: A promising therapeutical target for NAFLD and type 2 diabetes. Metabolism, 2018, 81, 71-82.
[http://dx.doi.org/10.1016/j.metabol.2017.12.001] [PMID: 29221790]
[14]
Zhu, Y.; Pu, Z.; Wang, G.; Li, Y.; Wang, Y.; Li, N.; Peng, F. FAM3C: An emerging biomarker and potential therapeutic target for cancer. Biomarkers Med., 2021, 15(5), 373-384.
[http://dx.doi.org/10.2217/bmm-2020-0179] [PMID: 33666514]
[15]
Song, C.; Duan, C. Upregulation of FAM3B promotes cisplatin resistance in gastric cancer by inducing epithelial-mesenchymal transition. Med. Sci. Monit., 2020, 26, e921002.
[http://dx.doi.org/10.12659/MSM.921002] [PMID: 32442162]
[16]
Lin, P.; Guo, Y.N.; Shi, L.; Li, X.J.; Yang, H.; He, Y.; Li, Q.; Dang, Y.W.; Wei, K.L.; Chen, G. Development of a prognostic index based on an immunogenomic landscape analysis of papillary thyroid cancer. Aging (Albany NY), 2019, 11(2), 480-500.
[http://dx.doi.org/10.18632/aging.101754] [PMID: 30661062]
[17]
Li, Z.; Mou, H.; Wang, T.; Xue, J.; Deng, B.; Qian, L.; Zhou, Y.; Gong, W.; Wang, J.M.; Wu, G.; Zhou, C.F.; Fang, J.; Le, Y. A non-secretory form of FAM3B promotes invasion and metastasis of human colon cancer cells by upregulating Slug expression. Cancer Lett., 2013, 328(2), 278-284.
[http://dx.doi.org/10.1016/j.canlet.2012.09.026] [PMID: 23059759]
[18]
He, S.L.; Wang, W.P.; Yang, Y.S.; Li, E.M.; Xu, L.Y.; Chen, L.Q. FAM3B promotes progression of oesophageal carcinoma via regulating the AKT-MDM2-p53 signalling axis and the epithelial-mesenchymal transition. J. Cell. Mol. Med., 2019, 23(2), 1375-1385.
[http://dx.doi.org/10.1111/jcmm.14040] [PMID: 30565387]
[19]
Maciel-Silva, P.; Caldeira, I.; de Assis Santos, I.; Carreira, A.C.O.; Siqueira, F.R.; Antonioli, E.; Goldberg, A.C.; Belizário, J.E.; Garay-Malpartida, H.M. FAM3B/PANDER inhibits cell death and increases prostate tumor growth by modulating the expression of Bcl-2 and Bcl-XL cell survival genes. BMC Cancer, 2018, 18(1), 90.
[http://dx.doi.org/10.1186/s12885-017-3950-9] [PMID: 29357840]
[20]
Solmi, R.; De Sanctis, P.; Zucchini, C.; Ugolini, G.; Rosati, G.; Del Governatore, M.; Coppola, D.; Yeatman, T.J.; Lenzi, L.; Caira, A.; Za-notti, S.; Taffurelli, M.; Carinci, P.; Valvassori, L.; Strippoli, P. Search for epithelial-specific mRNAs in peripheral blood of patients with colon cancer by RT-PCR. Int. J. Oncol., 2004, 25(4), 1049-1056.
[http://dx.doi.org/10.1016/j.hoc.2004.06.011] [PMID: 15375555]
[21]
Huang, H.; Zhang, L.; Fu, J.; Tian, T.; Liu, X.; Liu, Y.; Sun, H.; Li, D.; Zhu, L.; Xu, J.; Zheng, T.; Jia, C.; Zhao, Y. Development and vali-dation of 3-CpG methylation prognostic signature based on different survival indicators for colorectal cancer. Mol. Carcinog., 2021, 60(6), 403-412.
[http://dx.doi.org/10.1002/mc.23300] [PMID: 33826760]
[22]
Li, T.; Fu, J.; Zeng, Z.; Cohen, D.; Li, J.; Chen, Q.; Li, B.; Liu, X.S. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res., 2020, 48(W1), W509-W514.
[http://dx.doi.org/10.1093/nar/gkaa407] [PMID: 32442275]
[23]
Gao, J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; Cerami, E.; Sand-er, C.; Schultz, N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal., 2013, 6(269), pl1.
[http://dx.doi.org/10.1126/scisignal.2004088] [PMID: 23550210]
[24]
Tang, Z.; Li, C.; Kang, B.; Gao, G.; Li, C.; Zhang, Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res., 2017, 45(W1), W98-W102.
[http://dx.doi.org/10.1093/nar/gkx247] [PMID: 28407145]
[25]
Zong, W.X.; Rabinowitz, J.D.; White, E. Mitochondria and cancer. Mol. Cell, 2016, 61(5), 667-676.
[http://dx.doi.org/10.1016/j.molcel.2016.02.011] [PMID: 26942671]
[26]
Zhang, X.; Dong, Y.; Zhao, M.; Ding, L.; Yang, X.; Jing, Y.; Song, Y.; Chen, S.; Hu, Q.; Ni, Y. ITGB2-mediated metabolic switch in CAFs promotes OSCC proliferation by oxidation of NADH in mitochondrial oxidative phosphorylation system. Theranostics, 2020, 10(26), 12044-12059.
[http://dx.doi.org/10.7150/thno.47901] [PMID: 33204328]
[27]
Roskoski, R. Jr Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol. Res., 2018, 135, 239-258.
[http://dx.doi.org/10.1016/j.phrs.2018.08.013] [PMID: 30118796]
[28]
Kirkin, V.; Dikic, I. Ubiquitin networks in cancer. Curr. Opin. Genet. Dev., 2011, 21(1), 21-28.
[http://dx.doi.org/10.1016/j.gde.2010.10.004] [PMID: 21071203]
[29]
Tervonen, T.A.; Partanen, J.I.; Saarikoski, S.T.; Myllynen, M.; Marques, E.; Paasonen, K.; Moilanen, A.; Wohlfahrt, G.; Kovanen, P.E.; Klefstrom, J. Faulty epithelial polarity genes and cancer. Adv. Cancer Res., 2011, 111, 97-161.
[http://dx.doi.org/10.1016/B978-0-12-385524-4.00003-9] [PMID: 21704831]
[30]
Mittal, B.; Tulsyan, S.; Kumar, S.; Mittal, R.D.; Agarwal, G. Cytochrome P450 in cancer susceptibility and treatment. Adv. Clin. Chem., 2015, 71, 77-139.
[http://dx.doi.org/10.1016/bs.acc.2015.06.003] [PMID: 26411412]
[31]
Gonzalez, D.M.; Medici, D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci. Signal., 2014, 7(344), re8.
[http://dx.doi.org/10.1126/scisignal.2005189] [PMID: 25249658]
[32]
Gavrielatou, N.; Doumas, S.; Economopoulou, P.; Foukas, P.G.; Psyrri, A. Biomarkers for immunotherapy response in head and neck cancer. Cancer Treat. Rev., 2020, 84, 101977.
[http://dx.doi.org/10.1016/j.ctrv.2020.101977] [PMID: 32018128]
[33]
Wu, C.C.; Xiao, Y.; Li, H.; Mao, L.; Deng, W.W.; Yu, G.T.; Zhang, W.F.; Sun, Z.J. Overexpression of FAM3C is associated with poor prognosis in oral squamous cell carcinoma. Pathol. Res. Pract., 2019, 215(4), 772-778.
[http://dx.doi.org/10.1016/j.prp.2019.01.019] [PMID: 30683473]
[34]
Bakir, B.; Chiarella, A.M.; Pitarresi, J.R.; Rustgi, A.K. EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol., 2020, 30(10), 764-776.
[http://dx.doi.org/10.1016/j.tcb.2020.07.003] [PMID: 32800658]
[35]
Dong, S.M.; Sun, D.I.; Benoit, N.E.; Kuzmin, I.; Lerman, M.I.; Sidransky, D. Epigenetic inactivation of RASSF1A in head and neck can-cer. Clin. Cancer Res., 2003, 9(10 Pt 1), 3635-3640.
[http://dx.doi.org/10.1093/carcin/bgg126] [PMID: 14506151]
[36]
Sala, D.; Cunningham, T.J.; Stec, M.J.; Etxaniz, U.; Nicoletti, C.; Dall’Agnese, A.; Puri, P.L.; Duester, G.; Latella, L.; Sacco, A. The Stat3-Fam3a axis promotes muscle stem cell myogenic lineage progression by inducing mitochondrial respiration. Nat. Commun., 2019, 10(1), 1796.
[http://dx.doi.org/10.1038/s41467-019-09746-1] [PMID: 30996264]
[37]
Li, C.; Shi, Y.; Zuo, L.; Xin, M.; Guo, X.; Sun, J.; Chen, S.; Zhao, B.; Yang, Z.; Sun, Z.; Zhao, H. Identification of Biomarkers Associated with Cancerous Change in Oral Leukoplakia Based on Integrated Transcriptome Analysis. J. Oncol., 2022, 2022, 4599305.
[http://dx.doi.org/10.1155/2022/4599305] [PMID: 35096060]
[38]
Wang, W.; Wang, M.; Ahmed, M.M.S.; Zhao, Y.; Wu, H.; Musa, M.; Chen, X. FAM3B serves as a biomarker for the development and malignancy of oral lichen planus. Int. J. Gen. Med., 2022, 15, 763-776.
[http://dx.doi.org/10.2147/IJGM.S346617] [PMID: 35082524]