Notch1-Jagged1 Signaling Pathway in Oral Squamous Cell Carcinoma: Relation to Tumor Recurrence and Patient Survival

Heba A. Elhendawy; Nashwa AL-Zaharani; Ziad Ehab; Nahed Soliman; Afaf T. Ibrahiem

doi:10.3889/oamjms.2022.10200

Authors

Heba A. Elhendawy Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mansoura University, Mansoura City, Egypt
Nashwa AL-Zaharani Department of Pathology, Northern Border University, Arar City, KSA
Ziad Ehab El-Waha High School, Arar City, KSA
Nahed Soliman Department of Pathology, Faculty of Medicine, Helwan University, Helwan, Egypt
Afaf T. Ibrahiem Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura City, Egypt

DOI:

https://doi.org/10.3889/oamjms.2022.10200

Keywords:

Jagged1, Notch1, Oral squamous cell carcinoma, Recurrence, Survival

Abstract

BACKGROUND: Dysregulated Jagged1/Notch1 signaling has been implicated in a variety of carcinomas, but little is known about the expression and possible role of Jagged1 and Notch1 in patients with oral squamous cell carcinoma (OSCC).

AIM: We set out to examine the clinical significance of Notch1 and Jagged1 expression in OSCC.

METHODS: Specimens were obtained from 44 patients who underwent surgical resection of primary OSCC. Immunostaining was done for Notch1 and Jagged1. The utilized markers’ expressions were analyzed in respect to 3 years overall survival (OS) and disease-free survival (DFS).

RESULTS: Poor prognosis was significantly associated with high Notch1 expression, high Jagged1 expression, advanced TNM clinical stage (III and IV), presence of distant metastasis, presence of nodal involvement, large-sized tumors (≥4 cm), presence of lymphovascular invasion, higher grade carcinomas, high Notch1 and Jagged1 coexpression, and carcinomas aroused from tongue and palate. Notch1, Jagged1, histologic grade, and tumor site were the independent predictors of DFS, while Jagged1 expression, histologic grade, and tumor site were the independent predictors of 3 years OS.

CONCLUSION: Our findings imply that either high levels of Notch1 or Jagged1 expression, or combined combination of both are related with poor prognostic outcomes.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Blatt S, Krüger M, Ziebart T, Sagheb K, Schiegnitz E, Goetze E, et al. Biomarkers in diagnosis and therapy of oral squamous cell carcinoma: A review of the literature. J Craniomaxillofac Surg. 2017;45(5):722-30. https://doi.org/10.1016/j.jcms.2017.01.033 PMid:28318929 DOI: https://doi.org/10.1016/j.jcms.2017.01.033

Ogbureke KU, Weinberger PM, Looney SW, Li L, Fisher LW. Expressions of matrix metalloproteinase-9 (MMP-9), dentin sialophosphoprotein (DSPP), and osteopontin (OPN) at histologically negative surgical margins may predict recurrence of oral squamous cell carcinoma. Oncotarget. 2012;3(3):286-98. https://doi.org/10.18632/oncotarget.373 PMid:22410369 DOI: https://doi.org/10.18632/oncotarget.373

Gupta PB, Pastushenko I, Skibinski A, Blanpain C, Kuperwasser C. Phenotypic plasticity: Driver of cancer initiation, progression, and therapy resistance. Cell Stem Cell. 2019;24(1):65-78. https://doi.org/10.1016/j.stem.2018.11.011 PMid:30554963 DOI: https://doi.org/10.1016/j.stem.2018.11.011

Lee HW, Kim SJ, Choi IJ, Song J, Chun KH. Targeting Notch signaling by γ-secretase inhibitor I enhances the cytotoxic effect of 5-FU in gastric cancer. Clin Exp Metastasis. 2015;32(6):593-603. https://doi.org/10.1007/s10585-015-9730-5 PMid:26134677 DOI: https://doi.org/10.1007/s10585-015-9730-5

Kim D, Li R. Contemporary treatment of locally advanced oral cancer. Curr Treat Options Oncol. 2019;20(4):32. https://doi.org/10.1007/s11864-019-0631-8 PMid:30874958 DOI: https://doi.org/10.1007/s11864-019-0631-8

Sherbet GV. Notch Signalling in Carcinogenesis. Molecular Approach to Cancer Management. Londan: Academic Press; 2017. p. 81-8. DOI: https://doi.org/10.1016/B978-0-12-812896-1.00008-8

Kang SW, Rane NS, Kim SJ, Garrison JL, Taunton J, Hegde RS. Substrate-specific translocational attenuation during ER stress defines a pre-emptive quality control pathway. Cell. 2006;127(5):999-1013. https://doi.org/10.1016/j.cell.2006.10.032 PMid:17129784 DOI: https://doi.org/10.1016/j.cell.2006.10.032

Xiu MX, Liu YM, Kuang BH. The oncogenic role of Jagged1/Notch signaling in cancer. Biomed Pharmacother. 2020;129:110416. https://doi.org/10.1016/j.biopha.2020.110416 PMid:32593969 DOI: https://doi.org/10.1016/j.biopha.2020.110416

Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2006;107(6):2223-33. https://doi.org/10.1182/blood-2005-08-3329 PMid:16291593 DOI: https://doi.org/10.1182/blood-2005-08-3329

VanDussen KL, Carulli AJ, Keeley TM, Patel SR, Puthoff BJ, Magness ST, et al. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development. 2012;139(3):488-97. https://doi.org/10.1242/dev.070763 PMid:22190634 DOI: https://doi.org/10.1242/dev.070763

Mohamed SY, Kaf RM, Ahmed MM, Elwan A, Ashour HR, Ibrahim A. The prognostic value of cancer stem cell markers (Notch1, ALDH1, and CD44) in primary colorectal carcinoma. J Gastrointest Cancer. 2018;50(4):824-37. https://doi.org/10.1007/s12029-018-0156-6 PMid:30136202 DOI: https://doi.org/10.1007/s12029-018-0156-6

Yoshida R, Ito T, Hassan WA, Nakayama H. Notch1 in oral squamous cell carcinoma. Histol Histopathol. 2017;32(4):315-23. https://doi.org/10.14670/HH-11-821 PMid:27615693

Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 2005;8(1):13-23. https://doi.org/10.1016/j.ccr.2005.06.004 PMid:16023595 DOI: https://doi.org/10.1016/j.ccr.2005.06.004

Fu H, Ma C, Guan W, Cheng W, Feng F, Wang H. Expression of Notch 1 receptor associated with tumor aggressiveness in papillary thyroid carcinoma. Onco Targets Ther. 2016;9:1519-23. https://doi.org/10.2147/OTT.S98239 PMid:27042120 DOI: https://doi.org/10.2147/OTT.S98239

Greife A, Hoffmann MJ, Schulz WA. Consequences of disrupted notch signaling in bladder cancer. Eur Urol. 2015;68(1):3-4. https://doi.org/10.1016/j.eururo.2015.02.034 PMid:25791514 DOI: https://doi.org/10.1016/j.eururo.2015.02.034

Joo YH, Jung CK, Kim MS, Sun DI. Relationship between vascular endothelial growth factor and Notch1 expression and lymphatic metastasis in tongue cancer. Otolaryngol Head Neck Surg. 2009;140(4):512-8. https://doi.org/10.1016/j.otohns.2008.12.057 PMid:19328339 DOI: https://doi.org/10.1016/j.otohns.2008.12.057

Zou JH, Xue TC, Sun C, Li Y, Liu B Bin, Sun RX, et al. Prognostic significance of Hes-1, a downstream target of notch signaling in hepatocellular carcinoma. Asian Pacific J Cancer Prev. 2015;16(9):3811-6. https://doi.org/10.7314/apjcp.2015.16.9.3811 PMid:25987042 DOI: https://doi.org/10.7314/APJCP.2015.16.9.3811

Wang S, Fan H, Xu J, Zhao E. Prognostic implication of NOTCH1 in early stage oral squamous cell cancer with occult metastases. Clin Oral Investig. 2017;22(3):1131-8. https://doi.org/10.1007/s00784-017-2197-9 PMid:28866747 DOI: https://doi.org/10.1007/s00784-017-2197-9

Panelos J, Batistatou A, Paglierani M, Zioga A, Maio V, Santi R, et al. Expression of Notch-1 and alteration of the E-cadherin/β-catenin cell adhesion complex are observed in primary cutaneous neuroendocrine carcinoma (Merkel cell carcinoma). Mod Pathol. 2009;22(7):959-68. https://doi.org/10.1038/modpathol.2009.55 PMid:19396152 DOI: https://doi.org/10.1038/modpathol.2009.55

Zhang T, Liang L, Liu X, Wu J, Chen J, Su K, et al. TGFβ1-Smad3-Jagged1-Notch1–Slug signaling pathway takes part in tumorigenesis and progress of tongue squamous cell carcinoma. J Oral Pathol Med. 2016;45(7):486-93. https://doi.org/10.1111/jop.12406 PMid:26764364 DOI: https://doi.org/10.1111/jop.12406

Zhang TH, Liu HC, Zhu LJ, Chu M, Liang YJ, Liang LZ, et al. Activation of Notch signaling in human tongue carcinoma. J Oral Pathol Med. 2011;40(1):37-45. https://doi.org/10.1111/j.1600-0714.2010.00931.x PMid:20819128 DOI: https://doi.org/10.1111/j.1600-0714.2010.00931.x

Lowell S, Jones P, Le Roux I, Dunne J, Watt FM. Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters. Curr Biol. 2000;10(9):491-500. https://doi.org/10.1016/s0960-9822(00)00451-6 PMid:10801437 DOI: https://doi.org/10.1016/S0960-9822(00)00451-6

Watt FM, Estrach S, Ambler CA. Epidermal Notch signalling: Differentiation, cancer and adhesion. Curr Opin Cell Biol. 2008;20(2):171-9. https://doi.org/10.1016/j.ceb.2008.01.010 PMid:18342499 DOI: https://doi.org/10.1016/j.ceb.2008.01.010

Okuyama R, Tagami H, Aiba S. Notch signaling: Its role in epidermal homeostasis and in the pathogenesis of skin diseases. J Dermatol Sci. 2008;49(3):187-94. https://doi.org/10.1016/j.jdermsci.2007.05.017 PMid:17624739 DOI: https://doi.org/10.1016/j.jdermsci.2007.05.017

Upadhyay P, Nair S, Kaur E, Aich J, Dani P, Sethunath V, et al. Notch pathway activation is essential for maintenance of stem-like cells in early tongue cancer. Oncotarget. 2016;7(31):50437-49. https://doi.org/10.18632/oncotarget.10419 PMid:27391340 DOI: https://doi.org/10.18632/oncotarget.10419

Michifuri Y, Hirohashi Y, Torigoe T, Miyazaki A, Kobayashi J, Sasaki T, et al. High expression of ALDH1 and SOX2 diffuse staining pattern of oral squamous cell carcinomas correlates to lymph node metastasis. Pathol Int. 2012;62(10):684-9. https://doi.org/10.1111/j.1440-1827.2012.02851.x PMid:23005595 DOI: https://doi.org/10.1111/j.1440-1827.2012.02851.x

Ravindran G, Devaraj H. Aberrant expression of β-catenin and its association with ΔNp63, Notch-1, and clinicopathological factors in oral squamous cell carcinoma. Clin Oral Investig. 2011;16(4):1275-88. https://doi.org/10.1007/s00784-011-0605-0 PMid:21881870 DOI: https://doi.org/10.1007/s00784-011-0605-0

Gado A, Ebeid B, Abdelmohsen A, Axon A. Colorectal cancer in Egypt is commoner in young people: Is this cause for alarm? Alexanderia J Med. 2019;50(3):197-201. https://doi.org/101016/j.ajme201303003 DOI: https://doi.org/10.1016/j.ajme.2013.03.003

Almangush A, Mäkitie AA, Triantafyllou A, de Bree R, Strojan P, Rinaldo A, et al. Staging and grading of oral squamous cell carcinoma: An update. Oral Oncol. 2020;107:104799. https://doi.org/10.1016/j.oraloncology.2020.104799 PMid:32446214 DOI: https://doi.org/10.1016/j.oraloncology.2020.104799

Chu D, Wang W, Xie H, Li Y, Dong G, Xu C, et al. Notch1 expression in colorectal carcinoma determines tumor differentiation status. J Gastrointest Surg. 2008;13(2):253-60. https://doi.org/10.1007/s11605-008-0689-2 PMid:18777195 DOI: https://doi.org/10.1007/s11605-008-0689-2

Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A. 2008;105(17):6392-7. https://doi.org/10.1073/pnas.0802047105 PMid:18427106 DOI: https://doi.org/10.1073/pnas.0802047105

Santagata S, Demichelis F, Riva A, Varambally S, Hofer MD, Kutok JL, et al. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 2004;64(19):6854-7. https://doi.org/10.1158/0008-5472.CAN-04-2500 PMid:15466172 DOI: https://doi.org/10.1158/0008-5472.CAN-04-2500

Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, et al. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med. 2007;204(12):2935. https://doi.org/10.1084/jem.20071082 PMid:17984306 DOI: https://doi.org/10.1084/jem.20071082

Weckx A, Riekert M, Grandoch A, Schick V, Zöller JE, Kreppel M. Time to recurrence and patient survival in recurrent oral squamous cell carcinoma. Oral Oncol. 2019;94:8-13. https://doi.org/10.1016/j.oraloncology.2019.05.002 PMid:31178216 DOI: https://doi.org/10.1016/j.oraloncology.2019.05.002

Kim E, Davidson LA, Zoh RS, Hensel ME, Patil BS, Jayaprakasha GK, et al. Homeostatic responses of colonic LGR5 + stem cells following acute in vivo exposure to a genotoxic carcinogen. Carcinogenesis. 2016;37(2):206-14. https://doi.org/10.1093/carcin/bgv250 PMid:26717997 DOI: https://doi.org/10.1093/carcin/bgv250

Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23:1124-34. https://doi.org/10.1038/nm.4409 PMid:28985214 DOI: https://doi.org/10.1038/nm.4409

Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555-67. https://doi.org/10.1016/j.stem.2007.08.014 PMid:18371393 DOI: https://doi.org/10.1016/j.stem.2007.08.014

Goossens-Beumer IJ, Zeestraten EC, Benard A, Christen T, Reimers MS, Keijzer R, et al. Clinical prognostic value of combined analysis of Aldh1, Survivin, and EpCAM expression in colorectal cancer. Br J Cancer. 2014;110(12):2935-44. https://doi.org/10.1038/bjc.2014.226 PMid:24786601 DOI: https://doi.org/10.1038/bjc.2014.226

Lin JT, Chen MK, Yeh KT, Chang CS, Chang TH, Lin CY, et al. Association of high levels of jagged-1 and notch-1 expression with poor prognosis in head and neck cancer. Ann Surg Oncol. 2010;17(11):2976-83. https://doi.org/10.1245/s10434-010-1118-9 PMid:20517681 DOI: https://doi.org/10.1245/s10434-010-1118-9

Xiao HJ, Ji Q, Yang L, Li RT, Zhang C, Hou JM. Retracted: In vivo and in vitro effects of microRNA-124 on human gastric cancer by targeting JAG1 through the Notch signaling pathway. J Cell Biochem. 2018;119(3):2520-34. https://doi.org/10.1002/jcb.26413 PMid:28941308 DOI: https://doi.org/10.1002/jcb.26413

Choi JH, Park JT, Davidson B, Morin PJ, Shih IM, Wang TL. Jagged-1 and notch3 juxtacrine loop regulates ovarian tumor growth and adhesion. Cancer Res. 2008;68(14):5716-23. https://doi.org/10.1158/0008-5472.CAN-08-0001 PMid:18632624 DOI: https://doi.org/10.1158/0008-5472.CAN-08-0001

Diévart A, Beaulieu N, Jolicoeur P. Involvement of Notch1 in the development of mouse mammary tumors. Oncogene. 1999;18(44):5973-81. https://doi.org/10.1038/sj.onc.1202991 PMid:10557086 DOI: https://doi.org/10.1038/sj.onc.1202991

Tohda S, Nara N. Expression of notchl and jaggedl proteins in acute myeloid leukemia cells. Leuk Lymphoma. 2009;42(3):467-72. https://doi.org/103109/10428190109064603 PMid:11699411 DOI: https://doi.org/10.3109/10428190109064603

De Freitas Filho SA, Coutinho-Camillo CM, Oliveira KK, Bettim BB, Pinto CA, Kowalski LP, et al. Prognostic implications of ALDH1 and notch1 in different subtypes of oral cancer. J Oncol. 2021;2021 :6663720. https://doi.org/10.1155/2021/6663720 PMid: 33854547 DOI: https://doi.org/10.1155/2021/6663720