基质金属蛋白酶19在结直肠癌及其肝转移中的作用与预后价值

doi:10.3969/j.issn.1006-5725.2025.13.007

摘要/Abstract

摘要：

目的探究基质金属蛋白酶19（MMP-19）在结直肠癌（CRC）及肝转移（CRLM）中的功能及分子机制。方法整合并分析TCGA、GEO数据库中CRC及CRLM患者的转录组、单细胞数据与临床资料。通过RNA测序数据分析与MMP-19表达相关的生物学功能，并采用qRT-PCR、Western blot和免疫组织化学染色检测MMP-19在原发灶与肝转移灶中的表达差异。此外，通过体外功能实验验证MMP-19对结直肠癌细胞增殖、侵袭及迁移的作用。结果 MMP-19在CRC组织中呈高表达，且与CRC、CRLM患者的不良预后显著相关。测序结果及功能富集分析表明MMP-19参与上皮间质转化、氨基酸蛋白转运、细胞增殖、细胞外基质组织构成及MAPK信号通路等生物学功能。单细胞分析显示在CRC原发灶及肝转移灶中，MMP-19在巨噬细胞和树突状细胞的表达高于正常组织。体外实验证实，MMP-19可增强结直肠癌细胞的增殖、侵袭及迁移能力。结论 MMP-19可能通过诱导上皮间质转化及重塑免疫微环境，促进CRC的发生发展及增加术后复发及肝转移风险，有望成为CRC、CRLM诊断和治疗的新靶点。

关键词: 基质金属蛋白酶, 结直肠癌, 结直肠癌肝转移, 上皮间质转化

Abstract:

Objective To explore the function and molecular mechanisms of matrix metalloproteinase 19 （MMP-19） in colorectal cancer （CRC） and liver metastasis of CRC （CRLM）. Methods This study comprehensively analyzed transcriptomic data， single-cell data， and clinical information of CRC and CRLM patients retrieved from public databases， namely The Cancer Genome Atlas （TCGA） and Gene Expression Omnibus （GEO）. RNA sequencing analysis was carried out to identify biological functions associated with MMP-19 expression. The differential expression of MMP-19 between primary lesions and liver metastatic lesions was evaluated using quantitative real-time polymerase chain reaction （qRT-PCR）， Western blotting， and immunohistochemistry. In vitro functional assays were performed to validate the impact of MMP-19 on the proliferation， invasion， and migration of colorectal cancer cells. Results MMP-19 was highly expressed in CRC tissues and was significantly correlated with poor prognosis in both CRC and CRLM patients. Sequencing results and functional enrichment analysis demonstrated that MMP-19 is involved in epithelial-mesenchymal transition， amino acid and protein transport， cell proliferation， extracellular matrix organization， and the mitogen-activated protein kinase （MAPK） signaling pathway. Single-cell analysis revealed that the expression of MMP-19 in macrophages and dendritic cells was higher in both CRC primary tumors and liver metastases compared to normal tissues. In vitro experiments confirmed that MMP-19 enhances the proliferation， invasion， and migration capabilities of colorectal cancer cells. Conclusion MMP-19 has been shown to play a crucial role in promoting the development and progression of CRC. It increases the risk of postoperative recurrence and liver metastasis through inducing epithelial-mesenchymal transition and remodeling the immune microenvironment. Given these findings， MMP-19 emerges as a promising novel target for the diagnosis and treatment of both CRC and CRLM.

Key words: matrix metalloproteinases, colorectal cancer, colorectal cancer liver metastasis, epithelial-mesenchymal transition

中图分类号:

R735

何泽平,徐军明. 基质金属蛋白酶19在结直肠癌及其肝转移中的作用与预后价值[J]. 实用医学杂志, 2025, 41(13): 1987-1996.

Zeping HE,Junming XU. The role and prognostic value of matrix metalloproteinase 19 in colorectal cancer and its liver metastasis[J]. The Journal of Practical Medicine, 2025, 41(13): 1987-1996.

图/表 20

图1

图2

表1

表2

图 3

表3

表4

图 4

表5

表6

表7

表8

表9

表10

表11

表12

表13

表14

表15

表16

参考文献 27

[1]	YAN C， SHAN F， LI Z Y. ［Prevalence of colorectal cancer in 2020： A comparative analysis between China and the world］［J］. Zhonghua Zhong Liu Za Zhi， 2023， 45（3）： 221-229.
[2]	ZHOU H， LIU Z， WANG Y， et al. Colorectal liver metastasis： Molecular mechanism and interventional therapy ［J］. Signal Transduct Target Ther， 2022， 7（1）： 70. doi:10.1038/s41392-022-00922-2 doi: 10.1038/s41392-022-00922-2
[3]	PETRONI G， BUQUE A， COUSSENS L M， et al. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment ［J］. Nat Rev Drug Discov， 2022， 21（6）： 440-462. doi:10.1038/s41573-022-00415-5 doi: 10.1038/s41573-022-00415-5
[4]	PEZESHKIAN Z， NOBILI S， PEYRAVIAN N， et al. Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer ［J］. Cancers （Basel）， 2021， 13（24）：6226. doi:10.3390/cancers13246226 doi: 10.3390/cancers13246226
[5]	ZHAO W， WANG L， YANG J， et al. Endothelial cell-derived MMP19 promotes pulmonary fibrosis by inducing E（nd）MT and monocyte infiltration ［J］. Cell Commun Signal， 2023， 21（1）： 56. doi:10.1186/s12964-023-01040-4 doi: 10.1186/s12964-023-01040-4
[6]	DAI C， XU P， LIU S， et al. Long noncoding RNA ZEB1-AS1 affects paclitaxel and cisplatin resistance by regulating MMP19 in epithelial ovarian cancer cells ［J］. Arch Gynecol Obstet， 2021， 303（5）： 1271-1281. doi:10.1007/s00404-020-05858-y doi: 10.1007/s00404-020-05858-y
[7]	MULLER M， BECK I M， GADESMANN J， et al. MMP19 is upregulated during melanoma progression and increases invasion of melanoma cells ［J］. Mod Pathol， 2010， 23（4）： 511-521. doi:10.1038/modpathol.2009.183 doi: 10.1038/modpathol.2009.183
[8]	LETTAU I， HATTERMANN K， HELD-FEINDT J， et al. Matrix metalloproteinase-19 is highly expressed in astroglial tumors and promotes invasion of glioma cells ［J］. J Neuropathol Exp Neurol， 2010， 69（3）： 215-223. doi:10.1097/nen.0b013e3181ce9f67 doi: 10.1097/nen.0b013e3181ce9f67
[9]	LU J， KORNMANN M， TRAUB B. Role of Epithelial to Mesenchymal Transition in Colorectal Cancer ［J］. Int J Mol Sci， 2023， 24（19）：14815. doi:10.3390/ijms241914815 doi: 10.3390/ijms241914815
[10]	SINGH M， MORRIS V K， BANDEY I N， et al. Advancements in combining targeted therapy and immunotherapy for colorectal cancer ［J］. Trends Cancer， 2024， 10（7）： 598-609. doi:10.1016/j.trecan.2024.05.001 doi: 10.1016/j.trecan.2024.05.001
[11]	PARKHURST M， GOFF S L， LOWERY F J， et al. Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer： phase 2 trial interim results ［J］. Nat Med， 2024， 30（9）： 2586-2595. doi:10.1038/s41591-024-03109-0 doi: 10.1038/s41591-024-03109-0
[12]	PITTAYAPRUEK P， MEEPHANSAN J， PRAPAPAN O， et al. Role of Matrix Metalloproteinases in Photoaging and Photocarcinogenesis ［J］. Int J Mol Sci， 2016， 17（6）：868. doi:10.3390/ijms17060868 doi: 10.3390/ijms17060868
[13]	SHOARI A， ASHJA ARDALAN A， DIMESA A M， et al. Targeting Invasion： The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy ［J］. Biomolecules， 2024， 15（1）：35. doi:10.3390/biom15010035 doi: 10.3390/biom15010035
[14]	MENG LI M W. Expression and Clinical Characteristics of Matrix Metalloproteinases in Malignant Tu-mors ［J］. Advances in Clinical Medicine， 2022， 12（05）： 4355-60. doi:10.12677/acm.2022.125631 doi: 10.12677/acm.2022.125631
[15]	CRAIG V J， ZHANG L， HAGOOD J S， et al. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis ［J］. Am J Respir Cell Mol Biol， 2015， 53（5）： 585-600. doi:10.1165/rcmb.2015-0020tr doi: 10.1165/rcmb.2015-0020tr
[16]	YANG C， DONG X， SUN B， et al. Physical immune escape： Weakened mechanical communication leads to escape of metastatic colorectal carcinoma cells from macrophages ［J］. Proc Natl Acad Sci U S A， 2024， 121（22）： e2322479121. doi:10.1073/pnas.2322479121 doi: 10.1073/pnas.2322479121
[17]	CHEN H， ZHAI C， XU X， et al. Multilevel Heterogeneity of Colorectal Cancer Liver Metastasis ［J］. Cancers （Basel）， 2023， 16（1）：59. doi:10.3390/cancers16010059 doi: 10.3390/cancers16010059
[18]	SHASHA T， GRUIJS M， VAN EGMOND M. Mechanisms of colorectal liver metastasis development ［J］. Cell Mol Life Sci， 2022， 79（12）： 607. doi:10.1007/s00018-022-04630-6 doi: 10.1007/s00018-022-04630-6
[19]	LIU C， QU L， ZHAO C， et al. Extracellular gamma-synuclein promotes tumor cell motility by activating beta1 integrin-focal adhesion kinase signaling pathway and increasing matrix metalloproteinase-24， -2 protein secretion ［J］. J Exp Clin Cancer Res， 2018， 37（1）： 117. doi:10.1186/s13046-018-0783-6 doi: 10.1186/s13046-018-0783-6
[20]	WANG Y， YU S J， LI Y X， et al. Expression and clinical significance of matrix metalloproteinase-17 and -25 in gastric cancer ［J］. Oncol Lett， 2015， 9（2）： 671-676. doi:10.3892/ol.2014.2747 doi: 10.3892/ol.2014.2747
[21]	XIAO C， WANG Y， CHENG Q， et al. Increased expression of MMP17 predicts poor clinical outcomes in epithelial ovarian cancer patients ［J］. Medicine （Baltimore）， 2022， 101（34）： e30279. doi:10.1097/md.0000000000030279 doi: 10.1097/md.0000000000030279
[22]	ZHANG Y， WANG J， FAN Y， et al. MMP11 and MMP17 are potential biomarkers for uterine corpus endometrial carcinoma prognosis ［J］. Clin Transl Oncol， 2024， 26（3）： 653-663. doi:10.1007/s12094-023-03284-5 doi: 10.1007/s12094-023-03284-5
[23]	YU J， HE Z， HE X， et al. Comprehensive Analysis of the Expression and Prognosis for MMPs in Human Colorectal Cancer ［J］. Front Oncol， 2021， 11： 771099. doi:10.3389/fonc.2021.771099 doi: 10.3389/fonc.2021.771099
[24]	MI T， ZHANG Z， ZHANGHUANG C， et al. Doxycycline hydrochloride inhibits the progress of malignant rhabdoid tumor of kidney by targeting MMP17 and MMP1 through PI3K-Akt signaling pathway ［J］. Eur J Pharmacol， 2024， 964： 176291. doi:10.1016/j.ejphar.2023.176291 doi: 10.1016/j.ejphar.2023.176291
[25]	YIP C， FOIDART P， SOMJA J， et al. MT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib ［J］. Br J Cancer， 2017， 116（6）： 742-751. doi:10.1038/bjc.2017.23 doi: 10.1038/bjc.2017.23
[26]	PAOLILLO M， SCHINELLI S. Extracellular Matrix Alterations in Metastatic Processes ［J］. Int J Mol Sci， 2019， 20（19）：4947. doi:10.3390/ijms20194947 doi: 10.3390/ijms20194947
[27]	JIROUSKOVA M， ZBODAKOVA O， GREGOR M， et al. Hepatoprotective effect of MMP-19 deficiency in a mouse model of chronic liver fibrosis ［J］. PLoS One， 2012， 7（10）： e46271. doi:10.1371/journal.pone.0046271 doi: 10.1371/journal.pone.0046271

组别	细胞类型	细胞占比	MMP-19	F值	P值
肝转移灶	巨噬细胞	0.49	0.84 ± 1.04^a	1 125.38	8.08e^-234
肝转移灶旁正常组织		0.17	0.26 ± 0.66	1 125.38	8.08e^-234
原发位结直肠癌		0.22	0.41 ± 0.88^b	24.44	7.95e^-07
原发癌旁正常组织		0.15	0.27 ± 0.72	24.44	7.95e^-07
肝转移灶	树突状细胞	0.23	0.33 ± 0.72^c	190.874	7.247e^-43
肝转移灶旁正常组织		0.10	0.13 ± 0.44	190.874	7.247e^-43
原发位结直肠癌		0.23	0.33 ± 0.73^d	6.492	0.01
原发癌旁正常组织		0.15	0.21 ± 0.59	6.492	0.01

组别	复孔数	MMP-19（TPM）
Oe-MMP-19	3	806.40 ± 14.79^a
Nc-MMP-19	3	11.88 ± 1.91
Sh-MMP-19	3	0.70 ± 0.39^b

组别	复孔数	MMP?14	FN1	CDH1	SNAI1	MMP?17
Oe-MMP-19	3	43.45 ± 1.99^a	9.83 ± 0.55^b	95.83 ± 3.64^c	17.73 ± 1.04^d	22.70 ± 1.41^e
Nc-MMP-19	3	18.85 ± 2.90	3.49 ± 0.88	241.00 ± 11.81	12.25 ± 0.21	18.18 ± 1.15

组别	复孔数	MMP?24	ZEB1	MMP?17
Sh-MMP-19	3	1.81 ± 0.12^a	12.36 ± 0.82^b	12.09 ± 0.42^c
Nc-MMP-19	3	2.52 ± 0.26	15.20 ± 1.05	18.18 ± 1.15

组别	复孔数	MMP-19
T1	3	1.615 ± 0.50^a
N1	3	1.00
T2	3	3.63 ± 1.93^b
N2	3	1.00
T3	3	2.51 ± 0.74^c
N3	3	1.00
T4	3	1.03 ± 0.32^d
N4	3	1.00