The Role of MMP-9 and MMP-9 Inhibition in Different Types of Thyroid Carcinoma

“

TL;DR

This review summarizes evidence that MMP-9 is overexpressed in thyroid carcinoma tissues and serum, correlating with aggressive features such as lymph node metastasis, extrathyroidal invasion, and advanced TNM stage. Both natural compounds (e.g., curcumin, EGCG, quercetin) and synthetic inhibitors (e.g., SB-3CT, valproic acid) suppress MMP-9 activity, reducing tumor cell migration, invasion, and epithelial-mesenchymal transition in preclinical models. These findings suggest MMP-9 is a promising biomarker and therapeutic target for thyroid cancer, though clinical translation remains limited.

Full summary

4,096 CHARS

**Background** Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, is a zinc-dependent proteolytic enzyme that degrades extracellular matrix components and is implicated in tumor growth, invasion, metastasis, and angiogenesis. Thyroid carcinoma (TC) is the most common endocrine cancer, with rising incidence and mortality. Current diagnostic methods such as fine-needle aspiration are invasive and operator-dependent, while treatment options (surgery, radioiodine, chemotherapy) have limitations. This narrative review examines the role of MMP-9 as a biomarker and therapeutic target in TC, summarizing evidence from preclinical studies and clinical observations.

**Methods** The authors conducted a narrative review of the literature, compiling data from studies that measured MMP-9 expression in TC tissues, serum, plasma, or cell lines using immunohistochemistry (IHC), gelatin zymography, western blotting, RT-PCR, and ELISA. They also reviewed studies testing natural and synthetic MMP-9 inhibitors in TC cell lines and animal models. Key outcomes included MMP-9 expression levels, correlations with clinicopathological features, and effects of inhibition on tumor cell behavior (proliferation, migration, invasion, EMT, apoptosis).

**Key Results** - MMP-9 expression is significantly higher in TC tumor tissues versus non-tumor tissues. For example, in papillary thyroid cancer (PTC), IHC positive staining was 82.56% in tumor vs. 61.63% in non-tumor (p < 0.05) [91]; another study reported 57.83% vs. 2.41% (p < 0.001) [93]. Serum MMP-9 levels were elevated in PTC patients (median 79.45 ng/mL) compared to benign thyroid nodule (BTN) patients (47.35 ng/mL) and healthy controls (47.71 ng/mL) (p < 0.001) [84]. - Higher MMP-9 levels correlate with aggressive features: lymph node metastasis (p = 0.028 to p < 0.001 across studies), extrathyroidal invasion (p = 0.001 to p < 0.001), advanced TNM stage (p = 0.005 to p < 0.001), larger tumor size (p = 0.031 to p < 0.001), and distant metastasis (p = 0.003 to p = 0.034) [81,82,83,84,91,93,94,95,97,98,100,105]. - MMP-9 levels decrease after surgery: in DTC patients, serum levels dropped from 134.70 ± 32.52 preoperatively to 51.46 ± 18.34 one month postoperatively (p < 0.05) [98]; in PTC, levels declined from 299.98 ± 70.48 pre-op to 169.07 ± 64.16 at 12 months post-op (p < 0.05) [99]. - Natural inhibitors (curcumin, EGCG, quercetin, ginsenoside Rg3, mangiferin, etc.) suppress MMP-9 activity and reduce TC cell viability, migration, invasion, and EMT in vitro and in vivo. For instance, curcumin (12.5–50 μM) inhibited migration and EMT in K1 PTC cells [122]; EGCG (10–60 μM) reduced proliferation and motility in FB-2 PTC cells [130]; quercetin (100 μM) suppressed migration and invasion in BCPAP cells [133]. - Synthetic inhibitors (valproic acid, sevoflurane, celecoxib) also decrease MMP-9 expression and tumor aggressiveness. Valproic acid (0.1–5 mM) promoted redifferentiation in ATC 8305C cells [137]; sevoflurane (2.5%) inhibited migration and invasion in TPC-1 and IHH-4 cells [135]. - Several signaling pathways involving MMP-9 in TC were identified, including TR4/circ-FNLA/miR-149-5p, SOX12/POU2F1, DUXAP10/Akt/mTOR, and IL-17RB/ERK1/2 [107,108,109,119].

**Clinical Implications** MMP-9 is a promising biomarker for diagnosing TC, assessing metastatic potential, and predicting prognosis. Its measurement in serum or tissue could help stratify patients for appropriate therapy intensity, potentially reducing overtreatment in low-risk cases. MMP-9 inhibitors, particularly natural compounds with favorable safety profiles, represent potential adjuvant therapies to conventional treatments. However, most evidence comes from preclinical models; clinical trials are limited. The review notes that some studies found no significant correlation between MMP-9 and metastasis, possibly due to methodological differences (e.g., semi-quantitative IHC, serum vs. tissue samples). Future research should focus on developing selective, bioavailable MMP-9 inhibitors and validating their efficacy in clinical settings.