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BMC Cancer
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Cervical Cancer | Research

MUC1 promotes cervical squamous cell carcinoma through ERK phosphorylation-mediated regulation of ITGA2/ITGA3

Authors: Aiqin Zhao, Yunzhi Pan, Yingyin Gao, Zheng Zhi, Haiying Lu, Bei Dong, Xuan Zhang, Meiying Wu, Fenxia Zhu, Sufang Zhou, Sai Ma

Published in: BMC Cancer | Issue 1/2024

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Abstract

In contrast to the decreasing trends in developed countries, the incidence and mortality rates of cervical squamous cell carcinoma in China have increased significantly. The screening and identification of reliable biomarkers and candidate drug targets for cervical squamous cell carcinoma are urgently needed to improve the survival rate and quality of life of patients. In this study, we demonstrated that the expression of MUC1 was greater in neoplastic tissues than in non-neoplastic tissues of the cervix, and cervical squamous cell carcinoma patients with high MUC1 expression had significantly worse overall survival than did those with low MUC1 expression, indicating its potential for early diagnosis of cervical squamous cell carcinoma. Next, we explored the regulatory mechanism of MUC1 in cervical squamous cell carcinoma. MUC1 could upregulate ITGA2 and ITGA3 expression via ERK phosphorylation, promoting the proliferation and metastasis of cervical cancer cells. Further knockdown of ITGA2 and ITGA3 significantly inhibited the tumorigenesis of cervical cancer cells. Moreover, we designed a combination drug regimen comprising MUC1-siRNA and a novel ERK inhibitor in vivo and found that the combination of these drugs achieved better results in animals with xenografts than did MUC1 alone. Overall, we discovered a novel regulatory pathway, MUC1/ERK/ITGA2/3, in cervical squamous cell carcinoma that may serve as a potential biomarker and therapeutic target in the future.
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Literature
1.
Sung H, Ferlay J, Siegel RL, 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):209–49.PubMedCrossRef
2.
Guo M, Xu J, Du J. Trends in cervical cancer mortality in China from 1989 to 2018: an age-period-cohort study and joinpoint analysis. BMC Public Health. 2021;21(1):1329.PubMedPubMedCentralCrossRef
3.
Xia C, Dong X, Li H, Cao M, Sun D, He S, Yang F, Yan X, Zhang S, Li N, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl). 2022;135(5):584–90.PubMedCrossRef
4.
Wei M, Zhou W, Bi Y, Wang H, Liu Y, Zhang ZJ. Rising mortality rate of cervical Cancer in younger women in Urban China. J Gen Intern Med. 2019;34(2):281–4.PubMedCrossRef
5.
Ma Y, Di J, Bi H, Zhao Q, Qin T, Xu W, Liu Z, Yi N, Zhao J, Zhou D, et al. Comparison of the detection rate of cervical lesion with TruScreen, LBC test and HPV test: a real-world study based on population screening of cervical cancer in rural areas of China. PLoS ONE. 2020;15(7):e0233986.PubMedPubMedCentralCrossRef
6.
7.
8.
Dhanisha SS, Guruvayoorappan C, Drishya S, Abeesh P. Mucins: structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets. Crit Rev Oncol Hematol. 2018;122:98–122.PubMedCrossRef
9.
Breugelmans T, Oosterlinck B, Arras W, Ceuleers H, De Man J, Hold GL, De Winter BY, Smet A. The role of mucins in gastrointestinal barrier function during health and disease. Lancet Gastroenterol Hepatol. 2022;7(5):455–71.PubMedCrossRef
10.
Levitin F, Stern O, Weiss M, Gil-Henn C, Ziv R, Prokocimer Z, Smorodinsky NI, Rubinstein DB, Wreschner DH. The MUC1 SEA module is a self-cleaving domain. J Biol Chem. 2005;280(39):33374–86.PubMedCrossRef
11.
12.
Dhar P, McAuley J. The role of the cell surface mucin MUC1 as a barrier to infection and Regulator of inflammation. Front Cell Infect Microbiol. 2019;9:117.PubMedPubMedCentralCrossRef
13.
Bhatia R, Gautam SK, Cannon A, Thompson C, Hall BR, Aithal A, Banerjee K, Jain M, Solheim JC, Kumar S, et al. Cancer-associated mucins: role in immune modulation and metastasis. Cancer Metastasis Rev. 2019;38(1–2):223–36.PubMedPubMedCentralCrossRef
14.
Marimuthu S, Rauth S, Ganguly K, Zhang C, Lakshmanan I, Batra SK, Ponnusamy MP. Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression. Cancer Metastasis Rev. 2021;40(2):575–88.PubMedPubMedCentralCrossRef
15.
van Putten JPM, Strijbis K. Transmembrane Mucins: signaling receptors at the intersection of inflammation and Cancer. J Innate Immun. 2017;9(3):281–99.PubMedPubMedCentralCrossRef
16.
Liu B, Pan S, Xiao Y, Liu Q, Xu J, Jia L. LINC01296/miR-26a/GALNT3 axis contributes to colorectal cancer progression by regulating O-glycosylated MUC1 via PI3K/AKT pathway. J Exp Clin Cancer Res. 2018;37(1):316.PubMedPubMedCentralCrossRef
17.
Chaika NV, Gebregiworgis T, Lewallen ME, Purohit V, Radhakrishnan P, Liu X, Zhang B, Mehla K, Brown RB, Caffrey T, et al. MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proc Natl Acad Sci U S A. 2012;109(34):13787–92.PubMedPubMedCentralCrossRef
18.
Maeda T, Hiraki M, Jin C, Rajabi H, Tagde A, Alam M, Bouillez A, Hu X, Suzuki Y, Miyo M, et al. MUC1-C induces PD-L1 and Immune Evasion in Triple-negative breast Cancer. Cancer Res. 2018;78(1):205–15.PubMedCrossRef
19.
Lim SC, Zhang S, Ishii G, Endoh Y, Kodama K, Miyamoto S, Hayashi R, Ebihara S, Cho JS, Ochiai A. Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res. 2004;10(1 Pt 1):166–72.PubMedCrossRef
20.
Togami S, Nomoto M, Higashi M, Goto M, Yonezawa S, Tsuji T, Batra SK, Douchi T. Expression of mucin antigens (MUC1 and MUC16) as a prognostic factor for mucinous adenocarcinoma of the uterine cervix. J Obstet Gynaecol Res. 2010;36(3):588–97.PubMedCrossRef
21.
Toyoda S, Kita T, Sugiura A, Itani Y, Okada H, Nakamura S, Ohbayashi C. Cervical adenocarcinoma with stromal micropapillary pattern. Diagn Cytopathol. 2016;44(2):133–6.PubMedCrossRef
22.
Samouelian V, Revillion F, Alloy N, Lhotellier V, Leblanc E, Peyrat JP. Measurement of mRNA of 11 biomarkers by RT-PCR to detect lymph node involvement in cervical cancer. Int J Biol Markers. 2008;23(2):74–82.PubMedCrossRef
23.
Kong X, Ding LJ, Wang ZX. Mucin expression profile of benign and malignant cervical tissues and correlation with clinical-pathologic parameters. Eur J Gynaecol Oncol. 2017;38(3):350–5.PubMed
24.
Ma S, Lu C-C, Yang L-Y, Wang J-J, Wang B-S, Cai H-Q, Hao J-J, Xu X, Cai Y, Zhang Y, et al. ANXA2 promotes esophageal cancer progression by activating MYC-HIF1A-VEGF axis. J Experimental Clin cancer Research: CR. 2018;37(1):183.PubMedCentralCrossRef
25.
Li Z, Pan Y, Yao J, Gao Y, Qian Y, Zheng M, Ma S. ANXA2 as a novel substrate of FBXW7 promoting esophageal squamous cell carcinoma via ERK phosphorylation. Biochem Biophys Res Commun. 2023;649:93–100.PubMedCrossRef
26.
Zuñiga Martinez ML, López Mendoza CM, Tenorio Salazar J, García Carrancá AM. Cerbón Cervantes MA, Alcántara-Quintana LE: establishment, authenticity, and characterization of cervical cancer cell lines. Mol Cell Oncol. 2022;9(1):2078628.PubMedPubMedCentralCrossRef
27.
Pan Y, Liu J, Gao Y, Guo Y, Wang C, Liang Z, Wu M, Qian Y, Li Y, Shen J, et al. FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation. J Exp Clin Cancer Res. 2023;42(1):75.PubMedPubMedCentralCrossRef
28.
Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 2020;18(7):e3000410.PubMedPubMedCentralCrossRef
29.
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):W98–102.PubMedPubMedCentralCrossRef
30.
Moschos SJ, Sullivan RJ, Hwu WJ, Ramanathan RK, Adjei AA, Fong PC, Shapira-Frommer R, Tawbi HA, Rubino J, Rush TS 3, et al. Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight. 2018;3(4):e92352.PubMedPubMedCentralCrossRef
31.
Bowden SJ, Doulgeraki T, Bouras E, Markozannes G, Athanasiou A, Grout-Smith H, Kechagias KS, Ellis LB, Zuber V, Chadeau-Hyam M, et al. Risk factors for human papillomavirus infection, cervical intraepithelial neoplasia and cervical cancer: an umbrella review and follow-up mendelian randomisation studies. BMC Med. 2023;21(1):274.PubMedPubMedCentralCrossRef
32.
Burki TK. Therapeutic HPV vaccine for cervical intraepithelial neoplasia. Lancet Oncol. 2019;20(5):e250.PubMedCrossRef
33.
Tarique M, Naz H, Suhail M, Turan A, Saini C, Muhammad N, Shankar H, Zughaibi TA, Khan TH, Khanna N, et al. Differential expression of programmed death 1 (PD-1) on various immune cells and its role in human leprosy. Front Immunol. 2023;14:1138145.PubMedPubMedCentralCrossRef
34.
Seyedsadr M, Wang Y, Elzoheiry M, Shree Gopal S, Jang S, Duran G, Chervoneva I, Kasimoglou E, Wrobel JA, Hwang D, et al. IL-11 induces NLRP3 inflammasome activation in monocytes and inflammatory cell migration to the central nervous system. Proc Natl Acad Sci U S A. 2023;120(26):e2221007120.PubMedPubMedCentralCrossRef
35.
Zhang X, Kiapour N, Kapoor S, Khan T, Thamilarasan M, Tao Y, Cohen S, Miller R, Sobel RA, Markovic-Plese S. IL-11 induces encephalitogenic Th17 cells in multiple sclerosis and experimental autoimmune encephalomyelitis. J Immunol. 2019;203(5):1142–50.PubMedPubMedCentralCrossRef
36.
Mittal S, Ghosh I, Banerjee D, Singh P, Biswas J, Nijhawan R, Srinivasan R, Ray C, Basu P. Reproducibility of cervical intraepithelial neoplasia diagnosis on histological review of cervical punch biopsies from a visual inspection with acetic acid and HPV detection-based screening program. Int J Gynaecol Obstet. 2014;126(3):227–31.PubMedCrossRef
37.
Hwang H, Follen M, Guillaud M, Scheurer M, MacAulay C, MacAulay C, Staerkel GA, van Niekerk D, Yamal JM. Cervical cytology reproducibility and associated clinical and demographic factors. Diagn Cytopathol. 2020;48(1):35–42.PubMedCrossRef
38.
Williams A. Cervical cancer: what’s new in squamous cell neoplasia. Diagn Histopathology. 2021;27(12):478–82.CrossRef
39.
Volesky KD, El-Zein M, Franco EL, Brenner DR, Friedenreich CM, Ruan Y. Cancers attributable to infections in Canada. Prev Med. 2019;122:109–17.PubMedCrossRef
40.
Hisamuddin M, Rizvi I, Malik A, Nabi F, Hassan MN, Ali SM, Khan JM, Khan TH, Khan RH. Characterization of pH-induced conformational changes in recombinant DENV NS2B-NS3pro. Int J Biol Macromol. 2023;253(Pt 3):126823.PubMedCrossRef
41.
Gautam SK, Khan P, Natarajan G, Atri P, Aithal A, Ganti AK, Batra SK, Nasser MW, Jain M. Mucins as potential biomarkers for early detection of Cancer. Cancers (Basel) 2023, 15(6).
42.
Attallah AM, El-Far M, Ibrahim AR, El-Desouky MA, Omran MM, Elbendary MS, Attallah KA, Qura ER, Abdallah SO. Clinical value of a diagnostic score for colon cancer based on serum CEA, CA19-9, cytokeratin-1 and mucin-1. Br J Biomed Sci. 2018;75(3):122–7.PubMedCrossRef
43.
Buisine MP, Devisme L, Copin MC, Durand-Réville M, Gosselin B, Aubert JP, Porchet N. Developmental mucin gene expression in the human respiratory tract. Am J Respir Cell Mol Biol. 1999;20(2):209–18.PubMedCrossRef
44.
Munro EG, Jain M, Oliva E, Kamal N, Lele SM, Lynch MP, Guo L, Fu K, Sharma P, Remmenga S, et al. Upregulation of MUC4 in cervical squamous cell carcinoma: pathologic significance. Int J Gynecol Pathol. 2009;28(2):127–33.PubMedPubMedCentralCrossRef
45.
Malinda RR, Zeeberg K, Sharku PC, Ludwig MQ, Pedersen LB, Christensen ST, Pedersen SF. TGFβ signaling increases net Acid Extrusion, Proliferation and Invasion in Panc-1 Pancreatic Cancer cells: SMAD4 dependence and link to Merlin/NF2 Signaling. Front Oncol. 2020;10:687.PubMedPubMedCentralCrossRef
46.
Roy LD, Sahraei M, Subramani DB, Besmer D, Nath S, Tinder TL, Bajaj E, Shanmugam K, Lee YY, Hwang SI, et al. MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene. 2011;30(12):1449–59.PubMedCrossRef
47.
Khan TH, Srivastava N, Srivastava A, Sareen A, Mathur RK, Chande AG, Musti KV, Roy S, Mukhopadhyaya R, Saha B. SHP-1 plays a crucial role in CD40 signaling reciprocity. J Immunol (Baltimore Md: 1950). 2014;193(7):3644–53.CrossRef
48.
Hiraki M, Maeda T, Mehrotra N, Jin C, Alam M, Bouillez A, Hata T, Tagde A, Keating A, Kharbanda S, et al. Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer. Signal Transduct Target Ther. 2018;3:13.PubMedPubMedCentralCrossRef
49.
Haratake N, Ozawa H, Morimoto Y, Yamashita N, Daimon T, Bhattacharya A, Wang K, Nakashoji A, Isozaki H, Shimokawa M et al. MUC1-C is a common driver of Acquired Osimertinib Resistance in NSCLC. J Thorac Oncol 2023.
50.
Thathiah A, Blobel CP, Carson DD. Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 shedding. J Biol Chem. 2003;278(5):3386–94.PubMedCrossRef
51.
52.
53.
Woo JK, Choi Y, Oh SH, Jeong JH, Choi DH, Seo HS, Kim CW. Mucin 1 enhances the tumor angiogenic response by activation of the AKT signaling pathway. Oncogene. 2012;31(17):2187–98.PubMedCrossRef
54.
Bozkaya G, Korhan P, Cokaklı M, Erdal E, Sağol O, Karademir S, Korch C, Atabey N. Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis. Mol Cancer. 2012;11:64.PubMedPubMedCentralCrossRef
55.
Cooper J, Giancotti FG. Integrin signaling in Cancer: mechanotransduction, stemness, epithelial plasticity, and Therapeutic Resistance. Cancer Cell. 2019;35(3):347–67.PubMedPubMedCentralCrossRef
56.
Ma L, Sun Y, Li D, Li H, Jin X, Ren D. Overexpressed ITGA2 contributes to paclitaxel resistance by ovarian cancer cells through the activation of the AKT/FoxO1 pathway. Aging. 2020;12(6):5336–51.PubMedPubMedCentralCrossRef
57.
Zhu T, Chen R, Wang J, Yue H, Lu X, Li J. The prognostic value of ITGA and ITGB superfamily members in patients with high grade serous ovarian cancer. Cancer Cell Int. 2020;20:257.PubMedPubMedCentralCrossRef
58.
Li Y, Li F, Bai X, Li Y, Ni C, Zhao X, Zhang D. ITGA3 is Associated with Immune Cell Infiltration and serves as a favorable prognostic biomarker for breast Cancer. Front Oncol. 2021;11:658547.PubMedPubMedCentralCrossRef
59.
Zhang H, Cui X, Cao A, Li X, Li L. ITGA3 interacts with VASP to regulate stemness and epithelial-mesenchymal transition of breast cancer cells. Gene. 2020;734:144396.PubMedCrossRef
60.
Jin W, Liao X, Lv Y, Pang Z, Wang Y, Li Q, Liao Y, Ye Q, Chen G, Zhao K, et al. MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner. Cell Death Dis. 2017;8(8):e2980.PubMedPubMedCentralCrossRef
61.
Kalra AV, Campbell RB. Mucin overexpression limits the effectiveness of 5-FU by reducing intracellular drug uptake and antineoplastic drug effects in pancreatic tumours. Eur J Cancer. 2009;45(1):164–73.PubMedCrossRef
62.
Shukla SK, Purohit V, Mehla K, Gunda V, Chaika NV, Vernucci E, King RJ, Abrego J, Goode GD, Dasgupta A, et al. MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. Cancer Cell. 2017;32(1):71–e8777.PubMedPubMedCentralCrossRef
Metadata
Title
MUC1 promotes cervical squamous cell carcinoma through ERK phosphorylation-mediated regulation of ITGA2/ITGA3
Authors
Aiqin Zhao
Yunzhi Pan
Yingyin Gao
Zheng Zhi
Haiying Lu
Bei Dong
Xuan Zhang
Meiying Wu
Fenxia Zhu
Sufang Zhou
Sai Ma
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-024-12314-6

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