Open Access

ARTICLE

Identifying and validating MMP family members (MMP2, MMP9, MMP12, and MMP16) as therapeutic targets and biomarkers in kidney renal clear cell carcinoma (KIRC)

by KUNLUN LI¹, DANDAN LI², BARBOD HAFEZ^3,*, MOUNIR M. SALEM BEKHIT⁴, YOUSEF A. BIN JARDAN⁴, FARS KAED ALANAZI⁴, EHAB I. TAHA⁴, SAYED H. AUDA⁴, FAIQAH RAMZAN^5,*, MUHAMMAD JAMIL⁶

1 The Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China
2 Department of Pharmaceutical Engineering, Jiangsu Ocean University, Lianyungang, China
3 Department of Biological Engineering, University of Salford, Salford, UK
4 Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
5 Department of Animal and Poultry Production, Faculty of Veterinary and Animal Sciences, Gomal University, Dera Ismail Khan, Pakistan
6 Department of Arid Zone Research, PARC institute, Dera Ismail Khan, Pakistan

* Corresponding Authors: BARBOD HAFEZ. Email: ; FAIQAH RAMZAN. Email:

(This article belongs to the Special Issue: Cancer Metastasis)

Oncology Research 2024, 32(4), 737-752. https://doi.org/10.32604/or.2023.042925

Received 16 June 2023; Accepted 11 October 2023; Issue published 20 March 2024

Abstract

Kidney Renal Clear Cell Carcinoma (KIRC) is a malignant tumor that carries a substantial risk of morbidity and mortality. The MMP family assumes a crucial role in tumor invasion and metastasis. This study aimed to uncover the mechanistic relevance of the MMP gene family as a therapeutic target and diagnostic biomarker in Kidney Renal Clear Cell Carcinoma (KIRC) through a comprehensive approach encompassing both computational and molecular analyses. STRING, Cytoscape, UALCAN, GEPIA, OncoDB, HPA, cBioPortal, GSEA, TIMER, ENCORI, DrugBank, targeted bisulfite sequencing (bisulfite-seq), conventional PCR, Sanger sequencing, and RT-qPCR based analyses were used in the present study to analyze MMP gene family members to accurately determine a few hub genes that can be utilized as both therapeutic targets and diagnostic biomarkers for KIRC. By performing STRING and Cytohubba analyses of the 24 MMP gene family members, MMP2 (matrix metallopeptidase 2), MMP9 (matrix metallopeptidase 9), MMP12 (matrix metallopeptidase 12), and MMP16 (matrix metallopeptidase 16) genes were denoted as hub genes having highest degree scores. After analyzing MMP2, MMP9, MMP12, and MMP16 via various TCGA databases and RT-qPCR technique across clinical samples and KIRC cell lines, interestingly, all these hub genes were found significantly overexpressed at mRNA and protein levels in KIRC samples relative to controls. The notable effect of the up-regulated MMP2, MMP9, MMP12, and MMP16 was also documented on the overall survival (OS) of the KIRC patients. Moreover, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed that promoter hypomethylation pattern was associated with up-regulation of hub genes (MMP2, MMP9, MMP12, and MMP16). In addition to this, hub genes were involved in various diverse oncogenic pathways. The MMP gene family members (MMP2, MMP9, MMP12, and MMP16) may serve as therapeutic targets and prognostic biomarkers in KIRC.

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