Study of the regulatory network of MUC1 and tumor-associated proteins

doi:10.3969/j.issn.1674-8115.2022.08.007

Abstract

Abstract:

Objective ·To investigate the level of the expression of mucin 1 (MUC1) in different cancers and its impact on patient survival, and predict the possible mechanisms of MUC1 involvement in oncogenesis and tumor progression by analyzing the regulatory network of tumor-associated proteins that interact with MUC1. Methods ·The mRNA levels of MUC1 in 33 tumors and the relationship between the expression of MUC1 and patient survival were analyzed by using the GEPIA 2 online platform. MUC1-HA plasmids were transfected in HEK293T cells, and then MUC1-binding proteins were obtained by co-immunoprecipitation (Co-IP) experiments with HA antibody, which was later analyzed by liquid chromatography-tandem mass spectrometry (LCMS/MS). The subcellular localization, molecular function, diseases involved, biological process of MUC1-binding proteins and the regulatory network of interactions between these proteins were analyzed by using String 11.5 online platform. Results ·MUC1 was highly expressed in 9 kinds of tumors, including breast cancer, cervical cancer, diffuse large B-cell tumor, glioblastoma multiforme, brain lower grade glioma, ovarian carcinoma, pancreatic carcinoma, thymoma, and uterine corpus carcinoma. The relationship between MUC1 expression and overall survival in these 9 kinds of tumors was analyzed, and MUC1 expression was found to be negatively correlated with the overall survival. Higher MUC1 expression was related to significantly shorter survival time in 6 kinds of tumors, including breast cancer, cervical cancer, glioblastoma multiforme, brain lower grade glioma, pancreatic carcinoma, and thymoma. A total of 526 MUC1-binding proteins were detected by mass spectrometry analysis, and these proteins were mostly localized in organelles, cytoplasm, and membrane structures. The main molecular functions of these proteins included protein binding, ion binding, and enzymatic activity. They were primarily involved in anatomical entity diseases, cell proliferation diseases, metabolic diseases, and cancers. The related biological processes largely consisted of cellular stress, metabolism, development, and biosynthesis. MUC1-binding proteins played various roles in signaling pathways of metabolism, cancer, cGMP-cGMP-dependent protein kinase (PKG), tumor necrosis factor (TNF), and cell cycle. Further analysis of MUC1-binding-protein-associated signaling pathways revealed that they were heavily implicated in cancer-related signaling pathways such as Wnt/β-catenin, Notch, and cAMP on the one hand, and promoted tumor development by regulating metabolism, apoptosis, and cell cycle on the other hand. Conclusion ·MUC1 is highly expressed in a variety of tumor issues and is associated with poor prognosis of patients. MUC1 regulates cellular metabolism and plays a part in tumor-related signaling pathways possibly through protein interactions. This study innovatively identifies several new MUC1-binding proteins, which lay the foundation for further investigation of new biological functions of MUC1.

Key words: mucin 1 (MUC1), tumor, survival analysis, proteome, signaling pathway

CLC Number:

CHU Yunkai, LIAO Chunhua, DENG Huayun, HUANG Lei. Study of the regulatory network of MUC1 and tumor-associated proteins[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(8): 1024-1033.

Figures/Tables 5

Fig 1 Transcription levels of MUC1 in different tumor tissues

Fig 2 Relationship between MUC1 expression and OS in 9 kinds of cancers

Fig 3 Subcellular localization and molecular function of MUC1-binding proteins

Fig 4 Diseases, biological processes and signaling pathways associated with MUC1-binding proteins

Fig 5 Signaling pathways of MUC1-binding proteins

TrendMD

References 47

1	LI W, HAN Y, SUN C, et al. Novel insights into the roles and therapeutic implications of MUC1 oncoprotein via regulating proteins and non-coding RNAs in cancer[J]. Theranostics, 2022, 12(3): 999-1011.
2	LAKSHMANAN I, PONNUSAMY M P, MACHA M A, et al. Mucins in lung cancer: diagnostic, prognostic, and therapeutic implications [J]. J Thorac Oncol, 2015, 10(1): 19-27.
3	REN J, AGATA N, CHEN D, et al. Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents[J]. Cancer Cell, 2004, 5(2): 163-175.
4	MORI Y, AKITA K, TANIDA S, et al. MUC1 protein induces urokinase-type plasminogen activator (uPA) by forming a complex with NF-κB p65 transcription factor and binding to the uPA promoter, leading to enhanced invasiveness of cancer cells[J]. J Biol Chem, 2014, 289(51): 35193-35204.
5	LI Y, PANG Z, DONG X, et al. MUC1 induces M2 type macrophage influx during postpartum mammary gland involution and triggers breast cancer[J]. Oncotarget, 2017, 9(3): 3446-3458.
6	RAJABI H, AHMAD R, JIN C, et al. MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells[J]. Prostate, 2012, 72(15): 1659-1668.
7	JIN W, LIAO X, LV Y, et al. MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner[J]. Cell Death Dis, 2017, 8(8): e2980.
8	LV Y, CANG W, LI Q, et al. Erlotinib overcomes paclitaxel-resistant cancer stem cells by blocking the EGFR-CREB/GRβ-IL-6 axis in MUC1-positive cervical cancer[J]. Oncogenesis, 2019, 8(12): 70.
9	RAINA D, KOSUGI M, AHMAD R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells[J]. Mol Cancer Ther, 2011, 10(5): 806-816.
10	HUANG L, REN J, CHEN D, et al. MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation[J]. Cancer Biol Ther, 2003, 2(6): 702-706.
11	HUANG L, CHEN D, LIU D, et al. MUC1 oncoprotein blocks glycogen synthase kinase 3β-mediated phosphorylation and degradation of β-catenin[J]. Cancer Res, 2005, 65(22): 10413-10422.
12	LI Y, YI H, YAO Y, et al. The cytoplasmic domain of MUC1 induces hyperplasia in the mammary gland and correlates with nuclear accumulation of β-catenin[J]. PLoS One, 2011, 6(4): e19102.
13	HUANG L, LIAO X, BECKETT M, et al. MUC1-C oncoprotein interacts directly with ATM and promotes the DNA damage response to ionizing radiation[J]. Genes Cancer, 2010, 1(3): 239-250.
14	LIAO C, YU L, PANG Z, et al. WWP1 targeting MUC1 for ubiquitin-mediated lysosomal degradation to suppress carcinogenesis[J]. Signal Transduct Target Ther, 2021, 6(1): 297.
15	SZKLARCZYK D, GABLE A L, LYON D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets[J]. Nucleic Acids Res, 2018, 47(D1): D607-D613.
16	ASTER J C, PEAR W S, BLACKLOW S C. The varied roles of Notch in cancer[J]. Annu Rev Pathol, 2017, 12: 245-275.
17	WANG Y, ZHAI S, XING J, et al. LncRNA GAS5 promotes abdominal aortic aneurysm formation through regulating the miR-185-5p/ADCY7 axis[J]. Anticancer Drugs, 2022, 33(3): 225-234.
18	KINKL N, HAGEMAN G S, SAHEL J A, et al. Fibroblast growth factor receptor (FGFR) and candidate signaling molecule distribution within rat and human retina[J]. Mol Vis, 2002, 8: 149-160.
19	MARTÍNEZ-REYES I, CHANDEL N S. Mitochondrial TCA cycle metabolites control physiology and disease[J]. Nat Commun, 2020, 11(1): 102.
20	ROMEO S. ACAT2 as a novel therapeutic target to treat fatty liver disease[J]. J Intern Med, 2022, 292(2): 175-176.
21	VAMECQ J, ANDREOLETTI P, EL KEBBAJ R, et al. Peroxisomal acyl-CoA oxidase type 1: anti-inflammatory and anti-aging properties with a special emphasis on studies with LPS and argan oil as a model transposable to aging[J]. Oxid Med Cell Longev, 2018, 2018: 6986984.
22	RODIONOV R N, JARZEBSKA N, WEISS N, et al. AGXT2: a promiscuous aminotransferase[J]. Trends Pharmacol Sci, 2014, 35(11): 575-582.
23	PLAITAKIS A, LATSOUDIS H, SPANAKI C. The human GLUD2 glutamate dehydrogenase and its regulation in health and disease[J]. Neurochem Int, 2011, 59(4): 495-509.
24	PIAZZA G A, WARD A, CHEN X, et al. PDE5 and PDE10 inhibition activates cGMP/PKG signaling to block Wnt/β-catenin transcription, cancer cell growth, and tumor immunity[J]. Drug Discov Today, 2020, 25(8): 1521-1527.
25	ZOU T, LIU J, SHE L, et al. A perspective profile of ADCY1 in cAMP signaling with drug-resistance in lung cancer[J]. J Cancer, 2019, 10(27): 6848-6857.
26	GAO Z, LEI W I, LEE L T O. The role of neuropeptide-stimulated cAMP-EPACs signalling in cancer cells[J]. Molecules, 2022, 27(1): 311.
27	DONG Y, CHEN H, GAO J, et al. Molecular machinery and interplay of apoptosis and autophagy in coronary heart disease[J]. J Mol Cell Cardiol, 2019, 136: 27-41.
28	MCILWAIN D R, BERGER T, MAK T W. Caspase functions in cell death and disease[J]. Cold Spring Harb Perspect Biol, 2013, 5(4): a008656.
29	YUE J, LÓPEZ J M. Understanding MAPK signaling pathways in apoptosis[J]. Int J Mol Sci, 2020, 21(7): E2346.
30	PIWARSKI S A, THOMPSON C, CHAUDHRY A R, et al. The putative endogenous AHR ligand ITE reduces JAG1 and associated NOTCH1 signaling in triple negative breast cancer cells[J]. Biochem Pharmacol, 2020, 174: 113845.
31	FUJII W, NISHIMURA T, KANO K, et al. CDK7 and CCNH are components of CDK-activating kinase and are required for meiotic progression of pig oocytes[J]. Biol Reprod, 2011, 85(6): 1124-1132.
32	DEGREGORI J. The genetics of the E2F family of transcription factors: shared functions and unique roles[J]. Biochim Biophys Acta, 2002, 1602(2): 131-150.
33	REN J, BHARTI A, RAINA D, et al. MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90[J]. Oncogene, 2006, 25(1): 20-31.
34	AHMAD R, ALAM M, RAJABI H, et al. The MUC1-C oncoprotein binds to the BH3 domain of the pro-apoptotic BAX protein and blocks BAX function[J]. J Biol Chem, 2012, 287(25): 20866-20875.
35	FRUMAN D A, CHIU H, HOPKINS B D, et al. The PI3K pathway in human disease[J]. Cell, 2017, 170(4): 605-635.
36	CUI C, MERRITT R, FU L, et al. Targeting calcium signaling in cancer therapy[J]. Acta Pharm Sin B, 2017, 7(1): 3-17.
37	JIN C, RAJABI H, PITRODA S, et al. Cooperative interaction between the MUC1-C oncoprotein and the Rab31 GTPase in estrogen receptor-positive breast cancer cells[J]. PLoS One, 2012, 7(7): e39432.
38	RAJABI H, HIRAKI M, TAGDE A, et al. MUC1-C activates EZH2 expression and function in human cancer cells[J]. Sci Rep, 2017, 7(1): 7481.
39	MA J, RUBIN B K, VOYNOW J A. Mucins, mucus, and goblet cells[J]. Chest, 2018, 154(1): 169-176.
40	PARK J A, PARK S, CHOI J K, et al. Inhibition of MUC1-C increases ROS and cell death in mouse embryonic stem cells[J]. Int J Stem Cells, 2021, 14(2): 180-190.
41	HAGIWARA M, YASUMIZU Y, YAMASHITA N, et al. MUC1-C activates the BAF (mSWI/SNF) complex in prostate cancer stem cells[J]. Cancer Res, 2021, 81(4): 1111-1122.
42	AGATA N, AHMAD R, KAWANO T, et al. MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8[J]. Cancer Res, 2008, 68(15): 6136-6144.
43	CHEN Q, LI D, REN J, et al. MUC1 activates JNK1 and inhibits apoptosis under genotoxic stress[J]. Biochem Biophys Res Commun, 2013, 440(1): 179-183.
44	SUN C C, ZHOU Q, HU W, et al. Transcriptional E2F1/2/5/8 as potential targets and transcriptional E2F3/6/7 as new biomarkers for the prognosis of human lung carcinoma[J]. Aging (Albany NY), 2018, 10(5): 973-987.
45	TAN P Y, WEN L J, LI H N, et al. miR-548c-3p inhibits the proliferation, migration and invasion of human breast cancer cell by targeting E2F3[J]. Cytotechnology, 2020, 72(5): 751-761.
46	TYAGI A, AGARWAL C, AGARWAL R. Inhibition of retinoblastoma protein (Rb) phosphorylation at serine sites and an increase in Rb-E2F complex formation by silibinin in androgen-dependent human prostate carcinoma LNCaP cells: role in prostate cancer prevention[J]. Mol Cancer Ther, 2002, 1(7): 525-532.
47	EVAN G I, VOUSDEN K H. Proliferation, cell cycle and apoptosis in cancer[J]. Nature, 2001, 411(6835): 342-348.

[1]	LI Siyu, CHEN Ya, HU Wentao, DAI Yongming, WU Yingwei. Using diffusion-relaxation correlation spectroscopic imaging to assess the heterogeneity of head and neck tumors and identify occult lymph node metastasis [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1202-1213.
[2]	WU Lei, DU Fenglin, ZHAO Mingna, REN Yizhe, ZHANG Xianzhou, LOU Jiatao. Expression of PTPRN in lung adenocarcinoma and its mechanism of promoting tumor metastasis [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(7): 846-857.
[3]	WANG Rui, YUAN Ying, TAO Xiaofeng. Application value of synthetic magnetic resonance imaging in predicting cervical lymph node metastasis of oral cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(7): 900-909.
[4]	YANG Na, LIU Junli, BAI Jing, YANG Siyi, HAN Jiming, ZHANG Huahua. HENMT1 promotes the proliferation and migration of gastric cancer by activating the PI3K-AKT-mTOR signaling pathway [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 717-726.
[5]	TANG Kairan, FENG Chengling, HAN Bangmin. Integrated single-cell and transcriptome sequencing to construct a prognostic model of M2 macrophage-related genes in prostate cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(5): 549-561.
[6]	WAN Hongjin, HU Yibin, WANG Xin, ZHANG Kai, QIN An, MA Peixiang, MA Hui, ZHAO Jie. Neferine alleviates intervertebral disc degeneration through KEAP1/NRF2/GPX4 and NF-κB signaling pathways [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(3): 261-270.
[7]	MA Xiuzhen, ZHOU Ni, GUO Siqi, WANG Yuanyuan, MAI Ping. Cannabinoid receptor 1 promotes M1 polarization of macrophages through the Gα_i/o/RhoA signaling pathway in mice with acute lung injury [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 161-168.
[8]	ZHANG Boyuan, YAO Zhirong. Current research on UV-induced DNA damage and its role in promoting the development of skin malignancies [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 228-232.
[9]	WU Shiyi, CHEN Si, LIU Bohan, LIU Yuting, LIU Yiwen, HE Yiqing, DU Yan, ZHANG Guoliang, GUO Qian, GAO Feng, YANG Cuixia. Role of "HA coat" in modulating stemness and endocrine resistance in ER⁺ breast cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(10): 1298-1307.
[10]	LIU Jia, REN Lingjie, SHI Minmin, TANG Xiaomei, MA Fangfang, QIN Jiejie. Identification and evaluation of COL12A1 as a novel serological diagnostic marker in pancreatic ductal adenocarcinoma [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(10): 1342-1352.
[11]	PANDIT Roshan, LU Junyao, HE Liheng, BAO Yujie, JI Ping, CHEN Yingying, XU Jie, WANG Ying. Role of tumor necrosis factor-α in coronavirus disease 2019-associated kidney injury [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(1): 1-10.
[12]	MA Meili, TENG Jiajun, GAO Zhiqiang, SHI Chunlei, ZHONG Hua, HAN Baohui. Clinical and imaging analyses of primary mediastinal yolk sac tumor [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(9): 1155-1161.
[13]	HU Fei, CAI Xiaohan, CHENG Rui, JI Shiyu, MIAO Jiaxin, ZHU Yan, FAN Guangjian. Progress in translational research on immunotherapy for osteosarcoma [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(7): 814-821.
[14]	ZHANG Yesheng, YANG Yijing, HUANG Yiwen, SHI Longyu, WANG Manyuan, CHEN Sisi. Research progress in immune cells regulating drug resistance of tumor cells in tumor microenvironment [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(7): 830-838.
[15]	LI Ping, JIANG Huiru, YE Mengyue, WANG Yayu, CHEN Xiaoyu, YUAN Ancai, XU Wenjie, DAI Huimin, CHEN Xi, YAN Xiaoxiang, TU Shengxian, ZHENG Yuanqi, ZHANG Wei, PU Jun. Analysis of epidemiological characteristics of risk factors for cardiovascular diseases and malignant tumors based on the Shanghai community elderly cohort [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(5): 617-625.