黏蛋白1调控肿瘤细胞恶性特征的功能位点分析

doi:10.3969/j.issn.1674-8115.2024.11.004

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (11): 1370-1382.doi: 10.3969/j.issn.1674-8115.2024.11.004

• 论著 · 基础研究 • 上一篇

黏蛋白1调控肿瘤细胞恶性特征的功能位点分析

高珂星(), 廖春华, 李昇泽, 马双羽, 黄雷()

上海交通大学基础医学院组织胚胎学与遗传发育学系，上海 200025

收稿日期:2024-02-11 接受日期:2024-03-22 出版日期:2024-11-28 发布日期:2024-11-28
通讯作者: 黄雷 E-mail:xingke_gao@163.com;leihuang@shsmu.edu.cn
作者简介:高珂星（2000—），女，硕士生；电子信箱：xingke_gao@163.com。
基金资助:
国家自然科学基金(81874197);上海市科学技术委员会“科技创新行动计划”生物医药科技支撑专项(21S11901600)

Functional site analysis of mucin 1 in regulating the malignant characteristics of tumor cells

GAO Kexing(), LIAO Chunhua, LI Shengze, MA Shuangyu, HUANG Lei()

Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 200025, China

Received:2024-02-11 Accepted:2024-03-22 Online:2024-11-28 Published:2024-11-28
Contact: HUANG Lei E-mail:xingke_gao@163.com;leihuang@shsmu.edu.cn
Supported by:
National Natural Science Foundation of China(82372764);Biomedical Science and Technology Support Special Project in “Science and Technology Innovation Action Plan” by Science and Technology Commission of Shanghai Municipality(21S11901600)

摘要/Abstract

摘要：

目的·探究黏蛋白1（mucin 1，MUC1）调控肿瘤细胞增殖、迁移和干性维持的功能位点。方法·通过癌症基因组图谱（The Cancer Genome Atlas，TCGA）数据库分析寻找MUC1基因在不同癌症中的突变特征，对不同MUC1突变位点进行分析及定位，并按突变出现频率排序；通过Western blotting筛选出突变频率较高且蛋白稳定表达的MUC1突变体，利用乳腺癌细胞株BT549敲除MUC1细胞系和乳腺非转化细胞株MCF-10A，应用慢病毒表达系统构建MUC1野生型（MUC1-WT）和突变体稳定表达的细胞系。采用免疫荧光法检测不同MUC1突变体的细胞定位。以MUC1-WT为阳性对照、MUC1-AQA功能丧失突变体为阴性对照，对不同突变细胞的肿瘤生物学功能进行分析：通过细胞计数试剂盒-8（cell counting kit-8，CCK-8）及克隆形成实验检测细胞增殖能力；通过划痕实验及Transwell实验检测细胞迁移能力；通过成球实验检测细胞干性。使用PyMOL软件分析MUC1突变体结构定位并通过蛋白质对接软件（ZDOCK Server）进行分子对接分析。结果·在TCGA数据库中得到102个位于MUC1编码区的突变，其中P418S、S251R、V359I、N271S、N465H 5个错义突变出现频率较高且位于非数目可变串联重复序列（non-variable number of tandem repeats，non-VNTR）区域。进一步检测发现MUC1-S251R、N271S、V359I突变体可稳定表达；细胞定位分析发现这3个突变体主要分布于细胞质，同时细胞核也有一定的分布，核质比与野生型未见明显差异。表达不同MUC1突变体细胞的肿瘤生物学功能分析发现：① MUC1-WT高表达显著增强BT549和MCF-10A细胞的增殖能力；与MUC1-WT细胞相比，MUC1-AQA、S251R、N271S突变体细胞增殖能力下降，但MUC1-V359I突变体细胞与MUC1-WT细胞具有相似的增殖能力。② MUC1-WT高表达细胞的迁移能力显著增强，而MUC1-AQA细胞迁移能力减弱。在BT549细胞中，MUC1-S251R与MUC1-V359I突变体细胞迁移能力与MUC1-WT细胞相似，但MUC1-N271S细胞的迁移能力较MUC1-WT细胞降低。在MCF-10A细胞中，MUC1-N271S与MUC1-V359I细胞的迁移能力接近MUC1-WT细胞；但MUC1-S251R细胞较MUC1-WT细胞迁移能力显著下降。③ MUC1-WT高表达显著增强2种细胞的干性，而MUC1-AQA细胞干性丧失；MUC1-N271S、V359I与MUC1-WT具有相似的维持细胞干性的能力，而MUC1-S251R使细胞干性减弱。PyMOL软件分析结果显示，MUC1-N271S及V359I位于海胆精子蛋白-肠激酶-聚集蛋白（sperm protein-enterokinase-agarin，SEA）区域及附近，分别处于loop区及β-折叠处；分子对接结果显示，MUC1-WT及V359I与表皮生长因子受体（epidermal growth factor receptor，EGFR）胞外域形成复合物的稳定性强于MUC1-N271S和S251R，其稳定性排序为V359I>WT>N271S>S251R。结论·MUC1突变体对肿瘤细胞的生物学功能具有不同影响，其对增殖能力影响可能与EGFR信号通路相关。MUC1-V359I与MUC1-WT相似，并未影响MUC1对肿瘤细胞增殖、迁移及干性维持的作用；而MUC1-S251、N271位点可能参与细胞增殖和迁移的信号通路调控且MUC1-S251位点对维持细胞干性较为重要。

关键词: 黏蛋白1, 错义突变, 肿瘤, 细胞增殖, 细胞迁移, 细胞干性

Abstract:

Objective ·To identify the functional motifs of mucin 1 (MUC1) involved in regulating tumor cell proliferation, migration, and stemness maintenance. Methods ·Mutational characteristics of the MUC1 gene across different cancers were identified from The Cancer Genome Atlas (TCGA) database. Various MUC1 mutation sites were analyzed and localized, followed by ranking based on mutation frequency. Western blotting was used to screen high-frequency MUC1 mutants with stable protein expression. BT549 cell line with MUC1 knocked out and MCF-10A cell line were used to stably overexpress MUC1 wild-type (MUC1-WT) and mutants by using lentiviral technology. Immunofluorescence was used to detect the cellular localization of MUC1 mutants. Using MUC1-WT as a positive control and MUC1-AQA, a loss-of-function mutant, as a negative control, the biological functions of different MUC1 mutant cells were analyzed: cell proliferation ability was assessed by cell counting kit-8 (CCK-8) assay and colony formation assay; cell migration ability was evaluated by wound-healing and Transwell assays; cell stemness was examined by sphere formation assay. Structural localization of MUC1 mutants was analyzed by using PyMOL software, and molecular docking analysis was performed by using a protein docking software (ZDOCK Server). ·Results A total of 102 mutations located in the MUC1 coding region were identified in the TCGA database, among which five missense mutations (P418S, S251R, V359I, N271S, and N465H) exhibited higher frequencies and were located in the non-variable number of tandem repeats (non-VNTR) region. Further examination revealed that the MUC1-S251R, N271S, and V359I mutants could be stably expressed. The cellular localization assay indicated that these three mutants predominantly localized in the cytoplasm, but were also presented in the nucleus. The nuclear-to-cytoplasmic ratio showed minimal differences between MUC1-WT and the mutants. Analysis of the tumorigenic biological functions of the cells expressing different MUC1 mutants revealed that: ① High expression of MUC1-WT significantly enhanced the proliferation ability of both BT549 and MCF-10A cells; the proliferation of MUC1-AQA, S251R, and N271S mutant cells was decreased compared to MUC1-WT cells, while MUC1-V359I mutant cells exhibited a similar proliferative profile to MUC1-WT cells. ② The migration ability of MUC1-WT high-expressing cells was significantly enhanced, whereas MUC1-AQA cells demonstrated attenuated migration. In the BT549 cells, the migration ability of MUC1-S251R and V359I cells was similar to that of MUC1-WT cells, whereas MUC1-N271S cells showed reduced migration. In the MCF-10A cells, the migration ability of MUC1-N271S and MUC1-V359I cells was similar to that of MUC1-WT cells, whereas MUC1-S251R cells exhibited significantly decreased migration. ③ Stemness was enhanced in both cell types with high MUC1-WT expression, while MUC1-AQA cells lost stemness; the cells with MUC1-N271S, V359I and MUC1-WT showed comparable maintenance of stemness, whereas MUC1-S251R cells demonstrated compromised stemness. PyMOL software analysis unveiled that MUC1-N271S and V359I were located in or around the sperm protein-enterokinase-agarin (SEA) region, specifically in the loop region and the β-sheet, respectively. The molecular docking analysis revealed that the stability of the complex formed by MUC1-WT or V359I with the extracellular domain of epidermal growth factor receptor (EGFR) surpassed that of MUC1-N271S or S251R, indicating a stability hierarchy of V359I>WT>N271S>S251R. ·Conclusion MUC1 mutants exhibit diverse impacts on the biological functions of tumor cells, with their effects on proliferation correlating with the EGFR signaling pathway. MUC1-V359I is similar to MUC1-WT, indicating a negligible effect on tumor cell proliferation, migration, and stemness maintenance. Conversely, MUC1-S251 and N271 sites may be involved in the regulation of signaling pathways governing cell proliferation and migration and the MUC1-S251 site plays a critical role in maintaining cell stemness.

Key words: mucin 1 (MUC1), missense mutation, tumor, cell proliferation, cell migration, cell stemness

中图分类号:

R730.2

高珂星, 廖春华, 李昇泽, 马双羽, 黄雷. 黏蛋白1调控肿瘤细胞恶性特征的功能位点分析[J]. 上海交通大学学报（医学版）, 2024, 44(11): 1370-1382.

GAO Kexing, LIAO Chunhua, LI Shengze, MA Shuangyu, HUANG Lei. Functional site analysis of mucin 1 in regulating the malignant characteristics of tumor cells[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(11): 1370-1382.

图/表 9

表1 PCR引物序列

Tab 1 Primer sequences for PCR

Primer	Forward (5′→3′)	Reverse (5′→3′)
AQA	GCCTTGGCTGTCGCTCAGGCCCGCCGAAAGAAC	GTTCTTTCGGCGGGCCTGAGCGACAGCCAAGGC
S251R	CCTCCAATCACAGGACTTCTCCCCAG	CTGGGGAGAAGTCCTGTGATTGGAGG
N271S	TTCACATTTCAAGCCTCCAGTTTAATT	AATTAAACTGGAGGCTTGAAATGTGAA
V359I	ACGATCTCAGACATCAGCGTGAGTGAT	ATCACTCACGCTTACGTCTGAGATCGT
P418S	CAGCTGGACATCTTTTCAGCCCGGGAT	ATCCCGGGCTGAAAAGATGTCCAGCTG
N465H	TCTTACACACACCCAGCAGTGGCAGCC	GGCTGCCACTGCTGGGTGTGTGTAAGA

图1 TCGA数据库中 MUC1 突变位点来源、定位及频率分析Note： A. Proportion of MUC1 mutations in various tumor types. B. MUC1 protein consisting of N1, VNTR, N2, SEA, ED, TM, and CD domains. C. Location of 102 mutation sites in MUC1 protein. D. The mutation sites with a frequency of 1.95% or more in tumor samples.

Fig 1 Analysis of sources, positions, and frequencies of MUC1 mutation sites in the TCGA database

表2 14个 MUC1 高频突变体的信息

Tab 2 Information of 14 MUC1 mutants with high frequency

Mutant	Cancer type	Location	Frequency/%
P418S	Lung squamous cell carcinoma	CD	5.19
T112P	Bladder urothelial carcinoma/pancreatic adenocarcinoma	N1	4.55
P134A	Pancreatic adenocarcinoma/melanoma	VNTR	3.90
S251R	Esophagogastric cancer/stomach adenocarcinoma	N2	2.60
V359I	Colorectal adenocarcinoma/breast invasive carcinoma	ED	2.60
G33R	Cutaneous squamous cell carcinoma	N1	1.95
S55N	Uterine corpus endometrial carcinoma	N1	1.95
P102L	Stomach adenocarcinoma	N1	1.95
N271S	Breast invasive carcinoma	SEA	1.95
G305D	Stomach adenocarcinoma	SEA	1.95
D336Y	Lung adenocarcinoma	SEA	1.95
V359F	Breast invasive carcinoma	ED	1.95
P418L	Cutaneous squamous cell carcinoma	CD	1.95
N465H	Uterine corpus endometrioid carcinoma	CD	1.95

图2 MUC1-WT及其突变体在细胞中的蛋白表达水平Note： A/C/E. Western blotting was used to detect MUC1 protein expression levels in HEK293T cells (A), BT549 cells (C) and MCF-10A cells (E). B/D/F. Statistical analysis of MUC1 protein levels in HEK293T cells (B), BT549 cells (D) and MCF-10A cells (F). ①P<0.001, ②P=0.020, ③P=0.002.

Fig 2 Protein expression levels of MUC1-WT and mutants in the cells

图3 MUC1-WT及其突变体的细胞定位Note： A/B. Detection of cellular localization of MUC1 mutants by immunofluorescence in BT549 cells (A) and MCF-10A cells (B)(×600). C/D. Statistical analysis of MUC1 nuclear/cytoplasm ratio in BT549 cells (C) and MCF-10A cells (D).

Fig 3 Cellular localization of MUC1-WT and mutants

图4 MUC1-WT及其突变体对细胞增殖能力的影响Note： A/B. Growth curves of BT549 cells (A) and MCF-10A cells (B) expressing MUC1-WT or mutants detected by CCK-8. C/D. Colony formation analysis of BT549 cells expressing MUC1-WT or mutants. Representative crystal violet-stained images (C) and corresponding statistical analysis (D). E/F. Colony formation analysis of MCF-10A cells expressing MUC1-WT or mutants. Representative crystal violet-stained images (E) and corresponding statistical analysis (F). ①P<0.001, ②P=0.003, ③P=0.005, ④P=0.007, ⑤P=0.009.

Fig 4 Effect of MUC1-WT and mutants on cell proliferation

图5 MUC1-WT及其突变体对细胞迁移的影响Note： A/B. Wound healing assay of BT549 cells expressing MUC1-WT or mutants. Representative images of cells at 0 h and 48 h (A, ×200) and corresponding statistical analysis (B). C/D. Wound healing assay of MCF-10A cells expressing MUC1-WT or mutants. Representative images of cells at 0 h and 48 h (C, ×200) and corresponding statistical analysis (D). E/F. Transwell migration analysis of BT549 cells expressing MUC1-WT or mutants. Representative crystal violet-stained images (E, ×100) and corresponding statistical analysis (F). G/H. Transwell migration analysis of MCF-10A cells expressing MUC1-WT or mutants. Representative crystal violet-stained images (G, ×100) and corresponding statistical analysis (H). ①P<0.001, ②P=0.004, ③P=0.014, ④P=0.030, ⑤P=0.025, ⑥P=0.003, ⑦P=0.050, ⑧P=0.042.

Fig 5 Effect of MUC1-WT and mutants on cell migration

图6 MUC1-WT及其突变体对细胞干性的影响Note： A/B. Sphere formation assay of BT549 cells expressing MUC1-WT or mutants. Representative images of spheres (A, ×100) and corresponding statistical analysis (B). C/D. Sphere formation assay of MCF-10A cells expressing MUC1-WT or mutants. Representative images of spheres (C, ×200) and corresponding statistical analysis (D). ①P<0.001, ②P=0.004, ③P=0.007, ④P=0.002.

Fig 6 Effect of MUC1-WT and mutants on cell stemness

图7 SEA区域及附近的MUC1突变定位及相应突变体与EGFR-ECD的分子对接分析Note： A. PyMoL software was used to localize MUC1 mutants in or around the SEA domain. B?E. ZDOCK Server was used to analyze the molecular docking of MUC1-WT (B) and mutants (C, S251R; D, N271S; E, V359I) with EGFR-ECD. Green represents the MUC1-N region (before the GSVVV sequence), orange represents the MUC1-C region (after the GSVVV sequence), blue represents EGFR-ECD region, and yellow represents the localization of the mutation sites.

Fig 7 Analysis of localization of MUC1 mutation sites in or around the SEA domain and molecular docking of the mutants with EGFR-ECD

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黏蛋白1调控肿瘤细胞恶性特征的功能位点分析

Functional site analysis of mucin 1 in regulating the malignant characteristics of tumor cells

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