PRL-3 and MMP9 Expression and Epithelial-Mesenchymal Transition Markers in Circulating Tumor Cells From Patients With Colorectal Cancer: Potential Value in Clinical Practice

Overview

Journal Front Oncol

Specialty Oncology

Date 2022 May 16

PMID 35574414

Authors

Xiao-Cui Hong

Qi-Lian Liang

Man Chen

Hai-Xia Yang

Jie Huang

Si-Lin Yi

Zhen-Wei Wang

Hai-Yan Liang

Ding-Yue Zhang

Zeng-Yi Huang

Affiliations

Soon will be listed here.

Abstract

Objective: To evaluate the clinical correlation of epithelial-mesenchymal transition (EMT) with PRL-3 and MMP9 expression in the circulating tumor cells (CTCs) of patients with colorectal cancer (CRC).

Materials And Methods: Between January 2016 and December 2018, the EMT phenotype-based subsets of CTCs and the expression levels of PRL-3 and MMP9 in CTCs were identified, and their clinical values in 172 patients were evaluated. The CTCs were isolated, classified, and counted using the CanPatrol™ CTC filtration system. The CTC subsets (epithelial cells, mesenchymal cells and biphenotypic cells), as well as PRL-3 and MMP9 expression, were detected by RNA hybridization.

Results: CTCs were detected in 93.0% (160/172) of the included patients with CRC. Positive PRL-3 and MMP9 expression in CTC and M-CTC was found in 75.0% (102/136) and 80.8% (97/120) of the patients, respectively. The proportion of patients with positive PRL-3 and MMP9 expression in M-CTC was significantly associated with distant metastasis (p<0.05). The patients with ≥6 CTCs tended to show poorer progression-free survival (PFS) and overall survival (OS) rates (p=0.016, 0.02, respectively), and the patients with ≥3 M-CTC also showed poor PFS (p=0.0013). Additionally, the patients with positive PRL-3 and MMP9 expression in CTCs had significantly poorer PFS (p=0.0024) and OS (p=0.095) than the patients with negative PRL-3 and MMP9 expression. Multivariate Cox analysis uncovered that positive PRL-3 and MMP9 expression in CTCs may be an independent prognostic factor for worse PFS.

Conclusion: EMT phenotypes and CTC numbers can be used as prognostic indicators for metastasis and survival in patients with CRC, and the combination of PRL-3 and MMP9 expression in CTCs is a promising clinical marker for patients with CRC.

Citing Articles

Current biological implications and clinical relevance of metastatic circulating tumor cells.

Shahhosseini R, Pakmehr S, Elhami A, Shakir M, Alzahrani A, Al-Hamdani M Clin Exp Med. 2024; 25(1):7.

PMID: 39546080 PMC: 11567993. DOI: 10.1007/s10238-024-01518-6.

Biomarkers of lymph node metastasis in colorectal cancer: update.

Zhu X, Lin S, Xie J, Wang L, Zhang L, Xu L Front Oncol. 2024; 14:1409627.

PMID: 39328205 PMC: 11424378. DOI: 10.3389/fonc.2024.1409627.

Clinical application of liquid biopsy in colorectal cancer: detection, prediction, and treatment monitoring.

Tao X, Li Q, Zeng Y Mol Cancer. 2024; 23(1):145.

PMID: 39014366 PMC: 11250976. DOI: 10.1186/s12943-024-02063-2.

Protein Tyrosine Phosphatase PRL-3: A Key Player in Cancer Signaling.

Liu H, Li X, Shi Y, Ye Z, Cheng X Biomolecules. 2024; 14(3).

PMID: 38540761 PMC: 10967961. DOI: 10.3390/biom14030342.

Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody.

Loh A, Thura M, Gupta A, Tan S, Kuan K, Ang K Mol Ther Oncolytics. 2023; 30:153-166.

PMID: 37674627 PMC: 10477756. DOI: 10.1016/j.omto.2023.08.006.

References

Xing X, Lian S, Hu Y, Li Z, Zhang L, Wen X . Phosphatase of regenerating liver-3 (PRL-3) is associated with metastasis and poor prognosis in gastric carcinoma. J Transl Med. 2013; 11:309. PMC: 3878674. DOI: 10.1186/1479-5876-11-309. View

Wu M, Tzeng H, Wu C, Yueh T, Peng Y, Tsai C . Association of Matrix Metalloproteinase-9 rs3918242 Promoter Genotypes With Colorectal Cancer Risk. Anticancer Res. 2019; 39(12):6523-6529. DOI: 10.21873/anticanres.13867. View

Lee S, Han Y, Yun J, Lee C, Shin D, Ha Y . Phosphatase of regenerating liver-3 promotes migration and invasion by upregulating matrix metalloproteinases-7 in human colorectal cancer cells. Int J Cancer. 2011; 131(3):E190-203. DOI: 10.1002/ijc.27381. View

Walter L, Pujada A, Bhatnagar N, Bialkowska A, Yang V, Laroui H . Epithelial derived-matrix metalloproteinase (MMP9) exhibits a novel defensive role of tumor suppressor in colitis associated cancer by activating MMP9-Notch1-ARF-p53 axis. Oncotarget. 2016; 8(1):364-378. PMC: 5352126. DOI: 10.18632/oncotarget.13406. View

Groot Koerkamp B, Rahbari N, Buchler M, Koch M, Weitz J . Circulating tumor cells and prognosis of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer: a meta-analysis. Ann Surg Oncol. 2013; 20(7):2156-65. DOI: 10.1245/s10434-013-2907-8. View

Javaid S, Zhang J, Smolen G, Yu M, Wittner B, Singh A . MAPK7 Regulates EMT Features and Modulates the Generation of CTCs. Mol Cancer Res. 2015; 13(5):934-43. PMC: 4433453. DOI: 10.1158/1541-7786.MCR-14-0604. View

Lamouille S, Xu J, Derynck R . Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014; 15(3):178-96. PMC: 4240281. DOI: 10.1038/nrm3758. View

Wu S, Liu Z, Liu S, Lin L, Yang W, Xu J . Enrichment and enumeration of circulating tumor cells by efficient depletion of leukocyte fractions. Clin Chem Lab Med. 2015; 53(2):337. DOI: 10.1515/cclm-2015-5000. View

Duciel L, Gomez L, Kondratova M, Kuperstein I, Saule S . The Phosphatase PRL-3 Is Involved in Key Steps of Cancer Metastasis. J Mol Biol. 2019; 431(17):3056-3067. DOI: 10.1016/j.jmb.2019.06.008. View

10.

Bardelli A, Saha S, Sager J, Romans K, Xin B, Markowitz S . PRL-3 expression in metastatic cancers. Clin Cancer Res. 2003; 9(15):5607-15. View

11.

Kong L, Li Q, Wang L, Liu Z, Sun T . The value and correlation between PRL-3 expression and matrix metalloproteinase activity and expression in human gliomas. Neuropathology. 2007; 27(6):516-21. DOI: 10.1111/j.1440-1789.2007.00818.x. View

12.

Pastushenko I, Blanpain C . EMT Transition States during Tumor Progression and Metastasis. Trends Cell Biol. 2018; 29(3):212-226. DOI: 10.1016/j.tcb.2018.12.001. View

13.

Ksiazkiewicz M, Markiewicz A, Zaczek A . Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology. 2012; 79(4):195-208. DOI: 10.1159/000337106. View

14.

Alix-Panabieres C, Pantel K . Challenges in circulating tumour cell research. Nat Rev Cancer. 2014; 14(9):623-31. DOI: 10.1038/nrc3820. View

15.

Kolbl A, Jeschke U, Andergassen U . The Significance of Epithelial-to-Mesenchymal Transition for Circulating Tumor Cells. Int J Mol Sci. 2016; 17(8). PMC: 5000705. DOI: 10.3390/ijms17081308. View

16.

Al-Aidaroos A, Yuen H, Guo K, Zhang S, Chung T, Chng W . Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells. J Clin Invest. 2013; 123(8):3459-71. PMC: 4011027. DOI: 10.1172/JCI66824. View

17.

Wang W, Wan L, Wu S, Yang J, Zhou Y, Liu F . Mesenchymal marker and LGR5 expression levels in circulating tumor cells correlate with colorectal cancer prognosis. Cell Oncol (Dordr). 2018; 41(5):495-504. DOI: 10.1007/s13402-018-0386-4. View

18.

Sun W, Li G, Wan J, Zhu J, Shen W, Zhang Z . Circulating tumor cells: A promising marker of predicting tumor response in rectal cancer patients receiving neoadjuvant chemo-radiation therapy. Oncotarget. 2016; 7(43):69507-69517. PMC: 5342494. DOI: 10.18632/oncotarget.10875. View

19.

McInnes L, Jacobson N, Redfern A, Dowling A, Thompson E, Saunders C . Clinical implications of circulating tumor cells of breast cancer patients: role of epithelial-mesenchymal plasticity. Front Oncol. 2015; 5:42. PMC: 4341429. DOI: 10.3389/fonc.2015.00042. View

20.

Liu D, Xue L, Li J, Yang Q, Peng J . Epithelial-mesenchymal transition and GALC expression of circulating tumor cells indicate metastasis and poor prognosis in non-small cell lung cancer. Cancer Biomark. 2018; 22(3):417-426. DOI: 10.3233/CBM-170995. View