Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Nov 21:12:1030590.
doi: 10.3389/fonc.2022.1030590. eCollection 2022.

MMP1 acts as a potential regulator of tumor progression and dedifferentiation in papillary thyroid cancer

Jun Zhou  1 , Ming Xu  1 , Jie Tan  1 , Lin Zhou  1 , Fang Dong  1 , Tao Huang  1
Affiliations

MMP1 acts as a potential regulator of tumor progression and dedifferentiation in papillary thyroid cancer

Jun Zhou et al. Front Oncol. .

Abstract

Papillary thyroid cancer (PTC) is one of the malignancies with an excellent prognosis. However, in PTC, progression or dedifferentiation into poorly differentiated thyroid cancer (PDTC) or anaplastic thyroid cancer (ATC) extremely jeopardizes patients' prognosis. MMP1 is a zinc-dependent endopeptidase, and its role in PTC progression and dedifferentiation is unclear. In this study, transcriptome data of PDTC/ATC and PTC from the Gene Expression Omnibus and The Cancer Genome Atlas databases were utilized to perform an integrated analysis of MMP1 as a potential regulator of tumor progression and dedifferentiation in PTC. Both bulk and single-cell RNA-sequencing data confirmed the high expression of MMP1 in ATC tissues and cells, and further study verified that MMP1 possessed good diagnostic and prognostic value in PTC and PDTC/ATC. Up-regulated MMP1 was found to be positively related to more aggressive clinical characteristics, worse survival, extracellular matrix-related pathways, oncogenic immune microenvironment, more mutations, higher stemness, and more dedifferentiation of PTC. Meanwhile, in vitro experiments verified the high level of MMP1 in PDTC/ATC cell lines, and MMP1 knockdown and its inhibitor triolein could both inhibit the cell viability of PTC and PDTC/ATC. In conclusion, our findings suggest that MMP1 is a potential regulator of tumor progression and dedifferentiation in PTC, and might become a novel therapeutic target for PTC, especially for more aggressive PDTC and ATC.

Keywords: MMP1; anaplastic thyroid carcinoma; dedifferentiation; papillary thyroid cancer; poorly differentiated thyroid cancer.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flow diagram of this study. The details of data collection and analysis were exhibited in a flow diagram. GEO, the Gene Expression Omnibus; PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid cancer; PTC, papillary thyroid cancer; TCGA, The Cancer Genome Atlas.
Figure 2
Figure 2
The identification of MMP1. (A) TC samples from the GEO database included in this study; (B) PCA map between PDTC/ATC and PTC. The difference between PTC and PDTC/ATC samples was not very large. (C) Volcano plots exhibited the DEGs between PDTC/ATC and PTC. (D) List of DEGs between PDTC/ATC and PTC. (E). Heat map of MMP1 and another top 40 DEGs between PDTC/ATC and PTC. (F) Single-cell sequencing data in five ATC and six PTC patients. (G) Four basic types of cells in single cell sequencing data: tumor/epithelial cells, immune cells, endothelial cells and fibroblasts. (H) MMP1 expression in different cells. (I) Relative quantification of MMP1 expression level. GEO, the Gene Expression Omnibus; PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid cancer; PTC, papillary thyroid cancer; DEG, differentially expressed gene.
Figure 3
Figure 3
Clinical significance of MMP1 in PTC and PDTC/ATC. (A) The mRNA levels of MMP1 were up-regulated in PTC samples, which were downloaded from the TCGA database containing 58 paired PTC and normal tissue samples. (B) MMP1 was up-regulated in PTC samples, which were downloaded from the TCGA database containing 510 PTC samples and 58 normal tissue samples. (C) MMP1 effectively discriminated between PTC and normal tissues from the TCGA database. (D) MMP1 effectively discriminated between PDTC/ATC and PTC tissues from the GEO database. PTC patients with higher MMP1 levels harbor worse (E) PFS and (F) DFI. PDTC/ATC patients with higher MMP1 levels harbor worse (G) OS. (H) Forest plot of MMP1 in univariate logistic regression analyses of clinicopathological characteristics of the PTC patients from TCGA database. GEO, the Gene Expression Omnibus; PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid cancer; PTC, papillary thyroid cancer; TCGA, The Cancer Genome Atlas; AUC, the area under the curve; CI, confidence interval; vs., versus; HR, hazard ratio; PFS, progression-free survival; DFI, disease-free interval; OS, overall survival. ***P <0.001.
Figure 4
Figure 4
Enrichment analysis. GO (A) and GSEA (B) enrichment analyses of DEGs between PDTC/ATC and PTC samples. (C) Co-expression heatmap of top 10 positively associated genes and top 10 negatively associated genes with MMP1 form TGGA PTC samples. (D) GO and KEGG enrichment analyses of main associated genes of MMP1. GEO, the Gene Expression Omnibus; PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid cancer; PTC, papillary thyroid cancer; TCGA, The Cancer Genome Atlas; GO, Gene Ontology; GSEA, Gene set enrichment analysis; KEGG, Kyoto Encyclopedia of Genes and Genomes; NES, normalized enrichment score; BP, Biological Process; CC, Cellular Component; MF, Molecular Function; ***P <0.001.
Figure 5
Figure 5
Correlation analysis of the expression of MMP1 with complex immune infiltration level in PTC samples from TCGA. (A) The correlation-heatmap between the GSVA scores and immune cell infiltrates over the PTC samples; (B) Correlation scatters plot of MMP1 levels and ImmuneScore of PTC samples. Different analyses of the correlation between MMP1 levels and immune infiltration: ssGSEA (C), TIMER (D), and xCELL (E). PTC, papillary thyroid cancer; THCA, thyroid cancer. TCGA, The Cancer Genome Atlas; *P <0.05. # false discovery rate <0.05.
Figure 6
Figure 6
Analysis of the mutation, stemness, and differentiation. (A) Landscape of BRAF V600E-RAS score and thyroid differentiation score based on MMP1 levels in PTC samples from TCGA. MMP1 high group had higher BRS (B) and lower TDS (C). MMP1 was significantly positively correlated with the PTC stemness via both EREG.EXPss method (D) and DNAss method (E). MMP1 was significantly negatively correlated with most TDS genes in both the GEO cohort of PDTC/ATC and PTC (F) and TCGA cohort of PTC (G). GEO, the Gene Expression Omnibus; PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid cancer; PTC, papillary thyroid cancer; TCGA, The Cancer Genome Atlas; BRS, BRAF V600E-RAS score; TDS, thyroid differentiation score. *P <0.05, **P <0.01, ***p <0.001, and ****p <0.0001.
Figure 7
Figure 7
Exploration of MMP1 via in vitro experiments. (A) MMP1 was up-regulated in PDTC cell line KTC-1 and ATC cell line CAL-62. (B) MMP1 was significantly down-regulated in cells after transfection with MMP1 siRNA detected by western blot. (C) IC50 of triolein in different cell lines. Triolein (D) and MMP1 knockdown (E) inhibited colony formation in different cell lines. PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid cancer; PTC, papillary thyroid cancer; IC50, half-maximal inhibitory concentration. *P <0.05, **P <0.01, and ***p <0.001.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Aschebrook-Kilfoy B, Ward MH, Sabra MM, Devesa SS. Thyroid cancer incidence patterns in the united states by histologic type, 1992-2006. Thyroid. (2011) 21(2):125–34. doi: 10.1089/thy.2010.0021 - DOI - PMC - PubMed
    1. Haugen. 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid (2016) 26(1):1–133. doi: 10.1089/thy.2015.0020 - DOI - PMC - PubMed
    1. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med (1998) 338(5):297–306. doi: 10.1056/NEJM199801293380506 - DOI - PubMed
    1. Kitahara CM, Sosa JA. The changing incidence of thyroid cancer. Nat Rev Endocrinol (2016) 12(11):646–53. doi: 10.1038/nrendo.2016.110 - DOI - PMC - PubMed
    1. Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet. (2016) 388(10061):2783–95. doi: 10.1016/S0140-6736(16)30172-6 - DOI - PubMed