Published online Sep 21, 2026. doi: 10.3748/wjg.119277
Revised: February 6, 2026
Accepted: March 27, 2026
Published online: September 21, 2026
Processing time: 210 Days and 15.1 Hours
Matrix metalloproteinase 3 (MMP3) plays critical roles in tumor progression, but its function in colorectal cancer (CRC) remains incompletely understood.
To investigate MMP3 expression, its clinical significance, and molecular mechan
The Cancer Genome Atlas colon adenocarcinoma and rectal adenocarcinoma data
MMP3 was significantly upregulated in CRC tissues compared with normal tiss
Our findings demonstrate that MMP3 promotes CRC progression by regulating EPAS1, highlighting MMP3 as a potential prognostic biomarker and therapeutic target for CRC.
Core Tip: Matrix metalloproteinase 3 (MMP3) is significantly overexpressed in colorectal cancer (CRC) tissues and cells, which is closely associated with advanced tumor stage, lymph node metastasis, nerve invasion and worse overall survival. Functional experiments demonstrate that MMP3 promotes CRC cell proliferation, migration, and invasion and represses apoptosis. Using proteomic analysis and in vivo xenograft models, we identify and verify endothelial PAS domain protein 1 (EPAS1) as a critical downstream target of MMP3. MMP3 facilitates CRC progression by regulating EPAS1 expression, suggesting that MMP3 may serve as a novel prognostic biomarker and potential therapeutic target for CRC.
- Citation: Du BB, Qian ZP, Zhu CZ, Guan QL. Matrix metalloproteinase 3 facilitates colorectal cancer progression by enhancing cell proliferation and invasion. World J Gastroenterol 2026; 32(35): 119277
- URL: https://www.wjgnet.com/1007-9327/full/v32/i35/119277.htm
- DOI: https://dx.doi.org/10.3748/wjg.119277
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, ranking third in terms of incidence and second in mortality among all cancers[1]. According to the GLOBOCAN 2023 statistics, over 2 million new CRC cases and 1 million deaths are reported annually, imposing a substantial burden on global healthcare systems[2]. Despite advances in surgical resection, chemotherapy, and targeted therapy, the prognosis of patients with advanced CRC remains poor, with a 5-year overall survival rate of less than 15%[3]. The development and progression of CRC involve complex mole
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that mediate the degradation of extracellular matrix (ECM) components, playing essential roles in tissue remodeling, angiogenesis, and tumor progression[5]. MMP3, also known as stromelysin-1, can degrade various ECM proteins, such as proteoglycans, laminin, and fibronectin[6]. Accumulating evidence has shown that MMP3 is upregulated in multiple cancers, including breast cancer, lung cancer, and pancreatic cancer, and its overexpression is associated with tumor invasion, metastasis, and poor prognosis[7-9]. In CRC, several studies have reported abnormal MMP3 expression, but its specific role in regulating CRC cell malignant behaviors and the underlying molecular mechanisms remain unclear. As early as 2006, studies have demonstrated a relationship between MMP1-1607 ins/del G and MMP3-1612 ins/delA combined polymorphisms and risk of serrated adenoma, suggesting their potential role in the early steps of colorectal carcinogenesis[10]. Subsequent studies have reported that C/EBPβ upregulation promoted tumor cell invasion in an MMP3-dependent manner in vitro and was associated with metastatic status in CRC[11]. However, the downstream targets of MMP3 in CRC and their contributions to tumor progression have not been fully elucidated.
Given the conflicting evidence regarding the role of MMP3 in CRC and the insufficient clarity surrounding its down
Human CRC cell lines (SW480, SW620, HT-29, HCT116, LOVO) and normal colonic epithelial cell line NCM460 (ATCC) were authenticated via short tandem repeat profiling within 6 months. Cells were cultured in DMEM (Gibco) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin at 37 °C with 5% CO2, and passaged at 80%-90% confluence.
MMP3 mRNA levels in The Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) adenocarcinoma datasets were analyzed. For validation, 40 paired CRC tumor/adjacent normal tissues (≥ 5 cm from tumor, pathologically confirmed) were collected (Gansu Provincial People's Hospital), and a 90-case CRC tissue microarray (TMA, Shanghai Xinchao Biotechnology, Chip ID: HRec-Ade180Sur-04) was used. All samples had ethical approval (IRB No. 2025-341) and informed consent; clinicopathological data were extracted from records.
Total RNA was extracted from tissues and cells using TRIzol reagent (Invitrogen, United States). cDNA synthesis was performed with a Reverse Transcription Kit (Takara, Japan), and quantitative real-time PCR (qRT-PCR) was conducted using SYBR Green Master Mix (Applied Biosystems, United States) on a StepOnePlus Real-Time PCR System. MMP3, endothelial PAS domain protein 1 (EPAS1), PEDS1, TPP1, RPN1, PLOD3, and CYB5B mRNA levels were normalized to GAPDH.
Total protein was extracted from cells and tumor tissues using RIPA lysis buffer with protease inhibitors. Protein concentrations were measured using a BCA kit. Equal amounts of protein were separated by SDS-PAGE, transferred to PVDF membranes, blocked with 5% non-fat milk, and incubated with primary antibodies against MMP3, EPAS1, or GAPDH (internal control) at 4 °C overnight. After incubation with secondary antibodies, bands were visualized using an ECL detection system.
TMA sections and tissue sections were deparaffinized, rehydrated, and subjected to antigen retrieval. After blocking with 5% BSA, sections were incubated with primary antibodies against MMP3 (Abcam, ab52915) and EPAS1 (Abcam, ab243861) at 4 °C overnight, followed by incubation with secondary antibodies. Staining was visualized using DAB, and semi-quantitative scoring was performed based on staining intensity and positive cell percentage.
Three shMMP3 (shMMP3-1/2/3) and negative control shNC (Shanghai Jike Gene) were cloned into the pLKO.1 plasmid. Full-length MMP3 cDNA was inserted into the pcDNA3.1(+) vector (pcDNA3.1-MMP3). Cells were transfected with Lipofectamine 3000; stable SW620-shMMP3 cells were selected with puromycin (2 μg/mL, 2 weeks) and validated by qRT-PCR/western blot.
Wound healing: Cells were grown to confluence in serum-free DMEM, then scratched. The wound closure rate was calculated by measuring the scratch width at 0 and 24 hours.
Transwell assays: 5 × 104 cells (serum-free) in upper chamber; 10% FBS in lower. Cells that migrated after 24 hours were counted. To measure invasion, Transwells were coated with Matrigel, and cells that invaded through were counted after 24 hours.
Colony formation: A total of 500 cells/well (6-well plate) and cultured for 14 days. Cells were then fixed and stained with crystal violet. The number of colonies ≥ 50 cells were counted.
Apoptosis: Cells were stained with Annexin V-FITC/PI (BD Biosciences). Apoptosis was analyzed by flow cytometry (BD FACSCanto II).
SW620-shMMP3/shNC cells (3 replicates/group) were used. Proteins were digested via filter-aided sample preparation (FASP); peptides were analyzed by Easy-nLC 1200-timsTOF Pro (DIA mode). Data were processed using MaxQuant, and differentially expressed proteins (DEPs) (FC > 1.5/< 0.67, P < 0.05) were annotated via Gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG). PPI networks were generated using STRING/Cytoscape.
Female BALB/c nude mice (4-6 weeks) were injected subcutaneously with 1 × 107 SW620-shMMP3/shNC cells (1:1 PBS/Matrigel, n = 5/group). Tumor volume (length × width2/2) was measured every 3 days during the tumor growth period. After 21-days, all animals were sacrificed via intravenous injection of an overdose of pentobarbital sodium (150 mg/kg). Euthanasia was confirmed by the disappearance of heartbeat, spontaneous respiration and pupillary reflex. Tumor tiss
To begin, we assessed MMP3 mRNA expression profiles in COAD (Figure 1A) and READ (Figure 1B) datasets obtained from the Cancer Genome Atlas. To corroborate these in silico observations, we evaluated MMP3 expression in 40 paired specimens of CRC tumor tissue and adjacent non-tumor counterparts. Reverse transcription-PCR verified a significant upregulation of MMP3 mRNA in tumor tissues relative to matched normal controls (P < 0.05; Figure 1C). Consistent with this finding, immunohistochemical (IHC) staining of the same patient cohort revealed pronounced overexpression of MMP3 protein in tumor samples compared with adjacent normal tissues (Figure 1D). This finding was further substantiated by semi-quantitative scoring of a tumor microarray (TMA) comprising 90 CRC cases, which showed significantly elevated MMP3 expression in tumor tissues (P < 0.001; Figure 1E).
To investigate the clinical significance of MMP3, we analyzed its correlation with major clinicopathological characteristics in CRC patients. Increased MMP3 expression was significantly associated with larger tumor size, nerve invasion, advanced T stage, lymph node metastasis, and higher tumor-node-metastasis (TNM) stage (Table 1). No significant correlations were detected between MMP3 expression and patient sex, age, or vascular invasion. Notably, Kaplan-Meier survival analysis of the TMA cohort demonstrated that high MMP3 expression functioned as an adverse prognostic marker, predicting diminished 5-year overall survival (P < 0.05; Figure 1F).
| Characteristics | n | MMP3 expression | χ2 | P value | |
| Low | High | ||||
| Gender | |||||
| Male | 54 | 12 | 42 | 0.788 | 0.373 |
| Female | 36 | 11 | 25 | ||
| Age (years) | |||||
| ≤ 60 | 33 | 9 | 24 | 0.081 | 0.776 |
| > 60 | 57 | 14 | 43 | ||
| Tumor size (cm) | |||||
| ≤ 5 | 52 | 18 | 34 | 5.314 | 0.021 |
| > 5 | 38 | 5 | 33 | ||
| Mucinous cancer | |||||
| Yes | 12 | 2 | 10 | 0.575 | 0.448 |
| No | 78 | 21 | 57 | ||
| Pathological grading | |||||
| I/II | 73 | 20 | 53 | 0.689 | 0.406 |
| III/IV | 17 | 3 | 14 | ||
| Vascular invasion | |||||
| Yes | 33 | 11 | 22 | 1.657 | 0.198 |
| No | 57 | 12 | 45 | ||
| Nerve invasion | |||||
| Yes | 19 | 12 | 59 | 13.240 | 0.001 |
| No | 71 | 11 | 8 | ||
| T staging | |||||
| T1-T2 | 55 | 22 | 33 | 15.510 | 0.001 |
| T3-T4 | 35 | 1 | 34 | ||
| Lymph node status | |||||
| N0 | 23 | 16 | 7 | 28.107 | 0.001 |
| N1-N2 | 67 | 7 | 60 | ||
| pTNM staging | |||||
| I/II | 56 | 22 | 34 | 14.689 | 0.001 |
| III/IV | 34 | 1 | 33 | ||
To investigate the biological roles of MMP3 in CRC, we initially assessed its expression levels across a panel of five CRC cell lines (SW480, SW620, HT-29, HCT116, and LOVO) in comparison with the normal human colonic epithelial cell line NCM460. qRT-PCR and western blot analysis demonstrated that MMP3 expression was markedly upregulated in CRC cells at both the mRNA and protein levels (Figure 2A and B). We then performed gain- and loss-of-function experiments to define the biological significance of MMP3 in CRC progression. Three distinct short hairpin RNAs (shRNAs) targeting MMP3 (shMMP3-1, shMMP3-2, shMMP3-3) were transfected into SW620 and HCT116 cells, resulting in efficient MMP3 knockdown (Figure 2C). MMP3 silencing significantly reduced cell proliferation and colony formation capacity in SW620 and HCT116 cells, whereas MMP3 overexpression enhanced these malignant phenotypes in SW620 cells (Figure 2D). In wound healing assays, MMP3 knockdown impaired CRC cell migration, while its overexpression accelerated wound closure (Figure 2E). Transwell assays consistently showed that MMP3 silencing suppressed, and MMP3 overexpression promoted, the migratory and invasive capacities of CRC cells (Figure 2F). Colony formation assays further confirmed that MMP3 knockdown attenuated cell proliferation, while its overexpression facilitated this process (Figure 2G). Flow cytometric analysis revealed that MMP3 silencing increased the apoptotic cell population in SW620 and HCT116 cells, whereas MMP3 overexpression significantly reduced apoptosis of SW480 cells (Figure 2H).
To investigate the downstream regulatory landscape of MMP3 in CRC, we performed 4D-DIA proteomic sequencing in SW620 cells following shRNA-induced MMP3 knockdown (Figure 3A and B). The resulting volcano plot revealed a broad repertoire of differentially regulated proteins (DEPs). The expression of EPAS1, a key regulator of methylation modification, was significantly decreased upon MMP3 knockdown (Figures 3C and 4D). Cluster of Orthologous Groups analysis of DEPs indicated that MMP3 silencing predominantly affected pathways related to signal transduction mechanisms, posttranslational modification, protein turnover, chaperones, and metabolic regulation (Figure 3E). Subcellular localization prediction showed that DEPs were primarily distributed in the nucleus (31.07%) and cytoplasm (28.99%) (Figure 3F). Further Gene Ontology enrichment analysis demonstrated that the DEPs were strongly associated with methylation modification processes, including organelle organization, intracellular transport, and protein-binding functions (Figure 3G). Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that cell cycle progression and metabolic pathways were notably disrupted in MMP3-deficient cells, implying broader impacts on cellular homeostasis (Figure 3H). Protein-protein interaction (PPI) network analysis identified clusters of DEPs with dense interconnections, particularly centered on methylation modification-related proteins (Figure 3I). A focused PPI subnetwork constructed around EPAS1 emphasized its interactions with core components of the P53 signaling pathway and metabolic regulators (Figure 3K), reinforcing its potential role as a critical downstream effector of MMP3. Subsequent qRT-PCR validation confirmed that MMP3 knockdown decreased the expression of EPAS1, PEDS1, and TPP1, while upregulating RPN1, PLOD3, and CYB5B (Figure 3J). These findings aligned with our proteomic profiling data and further bolstered the regulatory connection between MMP3 and the P53 signaling cascade. Collectively, these findings suggest that MMP3 modulates metabolic products in CRC cells by regulating EPAS1 expression.
To validate the in vivo function of MMP3 in CRC, we established a subcutaneous xenograft model using SW620 cells with stable MMP3 knockdown (Figure 4). Tumors derived from the sh-MMP3 group exhibited significantly reduced volumes and slower growth rates compared with those in the negative control group, indicating that MMP3 is essential for efficient tumor progression (Figure 4A-C and G). IHC staining confirmed successful MMP3 knockdown, showing markedly decreased MMP3 and EPAS1 expression in tumor sections from the sh-MMP3 cohort (Figure 4D). TUNEL staining revealed a substantial increase in apoptotic cells within sh-MMP3 tumors, suggesting that MMP3 contributes to tumor cell survival (Figure 4E). Western blot analysis further validated these findings, demonstrating reduced protein levels of MMP3 and EPAS1 in tumor lysates from the MMP3-silenced group (Figure 4F). Collectively, these in vivo experimental results indicate that MMP3 promotes CRC growth by regulating EPAS1 expression. Interventions targeting MMP3 may disrupt this regulatory axis, reduce tumor cell survival, and enhance apoptotic cell death.
In this study, we demonstrate that MMP3 is consistently upregulated in CRC tissues, and this finding has been validated through multiple analytical approaches including TCGA COAD and READ datasets, 40 pairs of matched tumor and non-tumor clinical specimens, and a TMA containing 90 CRC cases. qRT-PCR demonstrated a statistically significant elevation in MMP3 mRNA levels in tumor tissues compared with non-tumor tissues with a significance level, while IHC staining of the same clinical cohort and semi-quantitative scoring of the TMA further confirmed robust overexpression of MMP3 protein in CRC tissues with a more stringent significance level. This pattern of MMP3 upregulation aligns with the well-established role of MMP family members in tumor progression, specifically their function in mediating ECM degradation, which serves as a rate-limiting step for tumor cell invasion and metastatic dissemination[12]. Notably, elevated MMP3 expression was significantly associated with aggressive clinicopathological features, including larger tumor size, nerve invasion, advanced T stage, advanced TNM stage, and lymph node metastasis, which collectively highlights the func
Kaplan-Meier survival analysis of the TMA cohort identified high MMP3 expression as an unfavorable prognostic factor for CRC patients, as it was associated with reduced 5-year overall survival with a significance level of P < 0.05. This prognostic significance of MMP3 in CRC is consistent with its documented role in other cancer types. Previous studies have shown increased MMP1 and MMP3 expression in breast cancer tissue compared with normal breast epithelium tissue[14]. In gastric cancer, silencing the JNK1/2-c-JUN pathway downregulated MMP3 expression, which may serve as a promising strategy to inhibit gastric cancer progression[15]. Furthermore, this finding extends prior investigations into the utility of MMP family members as prognostic biomarkers in CRC, as previous studies have linked MMP2 expression to reduced survival in CRC patients[16] and identified MMP7 as a predictor in liver metastasis of CRC[17]; these collective observations support the potential clinical utility of MMP3 for stratifying high-risk CRC patients. Such stratification could facilitate the implementation of personalized clinical care strategies, including more intensive surveillance protocols or aggressive adjuvant therapeutic regimens for patients with high MMP3 expression, and this approach is analogous to the clinical application of established CRC biomarkers such as KRAS and BRAF mutations, which guide treatment decision-making[18,19].
Loss-of-function and gain-of-function experiments were conducted to delineate the biological role of MMP3 in CRC. qRT-PCR and western blot analysis confirmed that MMP3 expression levels were significantly higher in CRC cell lines. Stable knockdown of MMP3 in SW620 and HCT116 cells using three distinct shRNAs resulted in a significant decrease in cell proliferation as assessed by colony formation assays, decreased cell migration as evaluated by wound healing assays, decreased cell invasion as measured by Transwell invasion assays, and a concomitant increase in apoptosis as detected by flow cytometry. Conversely, MMP3 overexpression in SW620 cells enhanced these malignant phenotypes, further confirming the pro-tumorigenic role of MMP3 in CRC. Beyond its canonical function in ECM degradation[20], MMP3 can regulate key cellular processes, including cell cycle progression and apoptosis, which are central pathways governing tumor growth. The attenuation of long-term cell proliferation following MMP3 knockdown mirrored observations in pancreatic cancer where tumor cell-derived MMP3 orchestrates Rac1b and tissue alterations that promote pancreatic adenocarcinoma[21]. Furthermore, MMP3-associated transcriptomic profiles can stratify the risk of biochemical recurrence in primary prostate cancer independently of conventional clinical features[22]. The induction of apoptosis following MMP3 silencing suggested that MMP3 modulates the balance between pro-apoptotic and anti-apoptotic molecules, a mechanism that is similar to the role of MMP13 in CRC, where MMP13 inhibits apoptosis through the ERK/NF-κB/MMP13 pathway[23].
We performed proteomic profiling using 4D-DIA sequencing in SW620 cells following MMP3 knockdown to identify downstream mediators of MMP3’s oncogenic effects and identified EPAS1, also known as hypoxia-inducible factor 2α (HIF-2α) and a key regulator of methylation modification, as a major downstream target of MMP3. MMP3 knockdown led to a significant reduction in EPAS1 expression (0.42-fold, P < 0.001), and this regulatory relationship was validated by qRT-PCR. EPAS1 is known to mediate critical cellular processes, including adaptation to hypoxic microenvironments, angiogenesis, and metabolic reprogramming[24,25], and these functions establish a mechanistic link between MMP3 and CRC progression. Functional enrichment analyses including GO and KEGG analyses showed that MMP3 silencing affected multiple cellular pathways, including signal transduction, posttranslational modification, and metabolism, and these pathways are tightly associated with the biological functions of EPAS1. GO enrichment analysis revealed significant enrichment for terms related to methylation modification, such as organelle organization and protein binding. These data suggest that MMP3 may regulate EPAS1 expression through epigenetic mechanisms; this hypothesis is consistent with reports in other diseases, such as lung cancer where MMP9 modulates DNA methyltransferase activity[26] and EPAS1 causes cartilage destruction by regulating crucial catabolic genes[27]. The disruptions in cell cycle progression and metabolic pathways identified by KEGG analysis aligned with the well-documented roles of EPAS1 in regulating cell proliferation and metabolic adaptation[28].
PPI network analysis further emphasized the interaction between EPAS1 and the P53 signaling pathway, and P53 is a pivotal tumor suppressor gene that is frequently dysregulated in CRC[29]. These observations suggest that the MMP3-EPAS1 axis may disrupt P53-mediated tumor suppression, and this mechanism echoes reports in kidney cancer where EPAS1 inhibits P53 activity[30] and ZNF3 regulates proliferation, migration and invasion through MMP1 and TWIST in CRC[31]. qRT-PCR validation confirmed that MMP3 knockdown resulted in downregulation of EPAS1, PEDS1, and TPP1 expression and upregulation of RPN1, PLOD3, and CYB5B expression; each of these molecules has established roles in CRC progression, including PLOD3, which is involved in the regulation of ECM stiffness[32] and CYB5B which modulates lipid metabolism[33], a process critical for maintaining tumor energy homeostasis.
In vivo validation of the MMP3-EPAS1 axis was conducted using a subcutaneous xenograft model, and tumors derived from SW620 cells with stable MMP3 knockdown exhibited significantly reduced volumes and growth rates compared with tumors derived from control cells. IHC staining of these xenograft tumors confirmed successful knockdown of MMP3 and concurrent downregulation of EPAS1. TUNEL staining revealed a substantial increase in apoptotic cell populations within MMP3-knockdown tumors, and western blot analysis further validated reduced expression of both MMP3 and EPAS1. These in vivo findings were consistent with the observations from in vitro experiments. Additionally, these results align with reports in nasopharyngeal carcinoma where MMP2 promotes tumor growth and metastasis through HIF-1α-mediated angiogenesis[34] and in breast cancer where MMP9 inhibition reduces angiogenesis[35]. These collective findings support the therapeutic potential of targeting the MMP3-EPAS1 axis in CRC.
This study has several limitations that should be addressed in future research. First, the clinical sample size is relatively modest, and multi-center validation with larger and more diverse cohorts is necessary to confirm the prognostic value of MMP3 in CRC, an approach that has been emphasized in prior studies focused on CRC biomarkers[36]. Second, while EPAS1 was identified as a downstream target of MMP3, rescue experiments involving EPAS1 overexpression in MMP3-silenced cells are required to formally establish EPAS1 as a mediator of MMP3’s oncogenic effects, and this type of experimental design is a standard approach to confirm causal relationships in molecular biology[37]. Third, the specific mechanisms underlying MMP3-mediated regulation of EPAS1, such as direct PPI or epigenetic modification, remain unclear and warrant further investigation using techniques including co-immunoprecipitation and chromatin immunoprecipitation[38].
In conclusion, this study demonstrates that MMP3 is significantly upregulated in CRC tissues, correlates with poor prognosis in CRC patients, and promotes malignant phenotypes in CRC, including cell proliferation, migration, invasion, and resistance to apoptosis through EPAS1downregulation; this regulatory axis disrupts critical cellular pathways including P53 signaling and metabolic regulation. These findings collectively establish MMP3 as both a prognostic biomarker and a potential therapeutic target in CRC, and they advance our understanding of the molecular mechanisms underlying CRC progression while laying the groundwork for the development of MMP3-targeted precision medicine strategies for CRC patients.
Our findings demonstrate that MMP3 promotes CRC progression by regulating EPAS1, highlighting MMP3 as a potential prognostic biomarker and therapeutic target for CRC.
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