Expression and prognostic value of mothers against decapentaplegic homolog 7 in head and neck squamous cell carcinoma

doi:10.7518/hxkq.2025.2024341

Abstract

Abstract:

Objective This study aimed to explore the biological functions and clinical value of mothers against decapentaplegic homolog (SMAD) 7 in head and neck squamous cell carcinoma (HNSCC) through bioinformatics analysis and basic experiments. Methods The expression of SMAD7 in HNSCC in public databases was studied. Western blot was used to detect the expression of SMAD7 in HNSCC cell lines and normal epithelial cells. The SMAD7 highly expressed HNSCC cell line HSC-4 was silenced, and CCK-8, Transwell assays, and cell scratch experiments were conducted to study the effect of SMAD7 on the biological functions of HSC-4 cells. HNSCC expression profile data were obtained from UCSC xena, and genes related to SMAD7 were selected for gene ontology and Kyoto encyclopedia of genes and genomes gene enrichment analysis, construction of a co-expression gene interaction network, and screening of related cell signaling pathways. Western blot was used to detect the expression changes of proteins in the related cell signaling pathways in HNSCC cells with silenced SMAD7. cBioPortal was utilized to analyze the mutation rate of the SMAD7 gene, and the MethSurv database was used to analyze the methylation level of the SMAD7 gene and its correlation with prognosis. The receiver operating characteristic curve was used to assess the diagnostic value of SMAD7 for HNSCC. TIMER2.0 was used to analyze the correlation between SMAD7 expression and immune cell infiltration. Results SMAD7 was highly expressed in HNSCC tumor tissues and some cell lines. Silencing the expression of SMAD7 can significantly inhibit the proliferation, migration, and invasion of cancer cells. Silencing SMAD7 can induce the downregulation of vascular cell adhesion molecule 1 (VCAM-1). The bioinformatics analysis showed that the mutation rate of the SMAD7 gene and the methylation level were significantly correlated with the prognosis of patients with HNSCC. The expression of SMAD7 was related to the level of immune cell infiltration in HNSCC. Conclusion SMAD7 promotes the proliferation, migration, and invasion of HNSCC cells by regulating the expression of VCAM-1. It may be a potential tumor biomarker and therapeutic target for HNSCC.

Key words: mothers against decapentaplegic homolog 7, head and neck squamous cell carcinoma, vascular cell adhesion molecule 1, diagnosis, immunotherapy

CLC Number:

R739.8

Zhao Haihui, Zhong Xiaojuan, Huang Yi, Fei Wei. Expression and prognostic value of mothers against decapentaplegic homolog 7 in head and neck squamous cell carcinoma[J]. West China Journal of Stomatology, 2025, 43(5): 660-670.

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References 36

[1]	Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007[J]. CA Cancer J Clin, 2007, 57(1): 43-66.
[2]	McGuire S. World Cancer Report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press, 2015[J]. Adv Nutr, 2016, 7(2): 418-419.
[3]	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[4]	Ayub B, Qureshi FA, Hassan NH, et al. Optimising head and neck cancer patient management: the crucial contributions of multidisciplinary tumour board decision-making[J]. Ecancermedicalscience, 2024, 18: 1710.
[5]	Caruntu A, Yang SF, Acero J. New insights for an advanced understanding of the molecular mechanisms in oral squamous cell carcinoma[J]. Int J Mol Sci, 2024, 25(13): 6964.
[6]	Chen W, Wu X, Hu J, et al. The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGA-T2, and SMAD7[J]. Cardiovasc Diabetol, 2024, 23(1): 21.
[7]	He H, Wang H, Chen X, et al. Treatment for type 2 diabetes and diabetic nephropathy by targeting Smad3 signaling[J]. Int J Biol Sci, 2024, 20(1): 200-217.
[8]	Li Y, Zhao Y, Zhong G, et al. Vascular smooth muscle cell-specific miRNA-214 deficiency alleviates simulated microgravity-induced vascular remodeling[J]. FASEB J, 2024, 38(1): e23369.
[9]	Li W, Bai P, Li W. UHRF1 inhibition mitigates vascular endothelial cell injury and ameliorates atherosclerosis in mice via regulating the SMAD7/YAP1 axis[J]. Mol Immunol, 2024, 170: 119-130.
[10]	Gong M, Guo Y, Dong H, et al. Trigonelline inhibits tubular epithelial-mesenchymal transformation in diabetic kidney disease via targeting Smad7[J]. Biomed Pharmacother, 2023, 168: 115747.
[11]	Huang C, Peng M, Zhong X, et al. The correlation between the expression of Smad2/3 and Smad7 proteins in blood neutrophils and asthma disease[J/OL]. Minerva Med, 2024. doi: 10.23736/S0026-4806.23.08756-6 .
[12]	Gaikwad AV, Eapen MS, Dey S, et al. TGF-β1, pSmad-2/3, Smad-7, and β-Catenin are augmented in the pulmonary arteries from patients with idiopathic pulmonary fibrosis (IPF): role in driving endothelial-to-mesenchymal transition (EndMT)[J]. J Clin Med, 2024, 13(4): 1160.
[13]	Liu C, Ni L, Li X, et al. SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signalling pathway in the absence of VHL[J]. Clin Transl Med, 2023, 13(11): e1468.
[14]	Luo H, Fu L, Wang X, et al. Salvianolic acid B ameliorates myocardial fibrosis in diabetic cardiomyopathy by deubiquitinating Smad7[J]. Chin Med, 2023, 18(1): 161.
[15]	Luiz-Ferreira A, Pacifico T, Cruz ÁC, et al. TRAIL-sensitizing effects of flavonoids in cancer[J]. Int J Mol Sci, 2023, 24(23): 16596.
[16]	Chen Z, Wang Y, Lu X, et al. The immune regulation and therapeutic potential of the SMAD gene family in breast cancer[J]. Sci Rep, 2024, 14(1): 6769.
[17]	Li Z, Zhao J, Wu Y, et al. TRAF2 decrease promotes the TGF-β-mTORC1 signal in MAFLD-HCC through enhancing AXIN1-mediated Smad7 degradation[J]. FA-SEB J, 2024, 38(4): e23491.
[18]	Colella M, Iannucci A, Maresca C, et al. SMAD7 sustains XIAP expression and migration of colorectal carcinoma cells[J]. Cancers (Basel), 2024, 16(13): 2370.
[19]	Chen J, Hu J, Li X, et al. Enhydrin suppresses the malignant phenotype of GBM via Jun/Smad7/TGF-β1 signaling pathway[J]. Biochem Pharmacol, 2024, 226: 116380.
[20]	Zhao Z, Zhang H, Zhang F, et al. Circular RNA sirtuin-1 restrains the malignant phenotype of non-small cell lung cancer cells via the microRNA-510-5p/SMAD family member 7 axis[J]. Acta Biochim Pol, 2023, 70(4): 855-863.
[21]	Dai T, Qiu S, Gao X, et al. Circular RNA circWNK1 inhibits the progression of gastric cancer via regulating the miR-21-3p/SMAD7 axis[J]. Cancer Sci, 2024, 115(3): 974-988.
[22]	Osborn L, Hession C, Tizard R, et al. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes[J]. Cell, 1989, 59(6): 1203-1211.
[23]	Kawano T, Yanoma S, Nakamura Y, et al. Evaluation of soluble adhesion molecules CD44 (CD44st, CD44v5, CD44v6), ICAM-1, and VCAM-1 as tumor markers in head and neck cancer[J]. Am J Otolaryngol, 2005, 26(5): 308-313.
[24]	Mazzoni A, Maggi L, Montaini G, et al. Human T cells interacting with HNSCC-derived mesenchymal stromal cells acquire tissue-resident memory like properties[J]. Eur J Immunol, 2020, 50(10): 1571-1579.
[25]	Jia M, Li Q, Guo J, et al. Deletion of BACH1 attenuates atherosclerosis by reducing endothelial inflammation[J]. Circ Res, 2022, 130(7): 1038-1055.
[26]	Zhang S, Xie B, Wang L, et al. Macrophage-mediated vascular permeability via VLA4/VCAM1 pathway dictates ascites development in ovarian cancer[J]. J Clin Invest, 2021, 131(3): 140315.
[27]	Pinho S, Wei Q, Maryanovich M, et al. VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells[J]. Nat Cell Biol, 2022, 24(3): 290-298.
[28]	Zhang D, Bi J, Liang Q, et al. VCAM1 promotes tumor cell invasion and metastasis by inducing EMT and transendothelial migration in colorectal cancer[J]. Front Oncol, 2020, 10: 1066.
[29]	Huang J, Deng Q, Wang Q, et al. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma[J]. Nat Genet, 2012, 44(10): 1117-1121.
[30]	Wang K, Zhang R, Li C, et al. Construction and assessment of an angiogenesis-related gene signature for prognosis of head and neck squamous cell carcinoma[J]. Discov Oncol, 2024, 15(1): 284.
[31]	Sato M, Enokida T, Fujisawa T, et al. Induction che-motherapy with paclitaxel, carboplatin, and cetuximab (PCE) followed by chemoradiotherapy for unresectable locoregional recurrence after curative surgery in patients with squamous cell carcinoma of the head and neck[J]. Front Oncol, 2024, 14: 1420860.
[32]	Lan HY. Diverse roles of TGF-β/Smads in renal fibrosis and inflammation[J]. Int J Biol Sci, 2011, 7(7):1056-1067.
[33]	Leone RD, Powell JD. Metabolism of immune cells in cancer[J]. Nat Rev Cancer, 2020, 20(9): 516-531.
[34]	Boschert V, Boenke J, Böhm AK, et al. Differential immune checkpoint protein expression in HNSCC: the role of HGF/MET signaling[J]. Int J Mol Sci, 2024, 25(13): 7334.
[35]	Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease[J]. Nature, 2013, 496(7446): 445-455.
[36]	Bronte V, Murray PJ. Understanding local macrophage phenotypes in disease: modulating macrophage function to treat cancer[J]. Nat Med, 2015, 21(2): 117-119.

临床病理特征		例数
年龄/岁	≥60	344
	<60	267
	未报道	1
性别	男	444
	女	168
饮酒史	无	197
	有	401
	未报道	14
抽烟史	无	255
	有	357
病理T分期	0	1
	1	52
	2	167
	3	122
	4	208
	未报道	62
临床分期	Ⅰ	23
	Ⅱ	120
	Ⅲ	137
	Ⅳ	318
	未报道	14
病理上淋巴结转移	无	206
	有	290
	未报道	116

慢病毒载体	靶点序列
control	5’-GCTTCGCGCCGTAGTCTTA-3’
sh1	5’-GGATATCTTCTATGATCTACC-3’
sh2	5’-GCCGAACCAGAACCAATTATT-3’
sh3	5’-GCTCAATGAGCATGTTTAGAC-3’