MTA2 as a Potential Biomarker and Its Involvement in Metastatic Progression of Human Renal Cancer by miR-133b Targeting MMP-9

Abstract

Metastasis-associated protein 2 (MTA2) was previously known as a requirement to maintain malignant potentials in several human cancers. However, the role of MTA2 in the progression of renal cell carcinoma (RCC) has not yet been delineated. In this study, MTA2 expression was significantly increased in RCC tissues and cell lines. Increased MTA2 expression was significantly associated with tumour grade (p = 0.002) and was an independent prognostic factor for overall survival with a high RCC tumour grade. MTA2 knockdown inhibited the migration, invasion, and in vivo metastasis of RCC cells without effects on cell proliferation. Regarding molecular mechanisms, MTA2 knockdown reduced the activity, protein level, and mRNA expression of matrix metalloproteinase-9 (MMP-9) in RCC cells. Further analyses demonstrated that patients with lower miR-133b expression had poorer survival rates than those with higher expression from The Cancer Genome Atlas database. Moreover, miR-133b modulated the 3 untranslated region (UTR) of MMP-9 promoter activities and subsequently the migratory and invasive abilities of these dysregulated expressions of MTA2 in RCC cells. The inhibition of MTA2 could contribute to human RCC metastasis by regulating the expression of miR-133b targeting MMP-9 expression.

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process

“…The expression and/or activity of MMP-9 are increased in different types of human tumors, playing a major role in their progression [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. In particular, MMP-9 is pivotal in all steps of the metastatic process, in that it strongly contributes to the ability that cancer cells have to: (1) disrupt the cell-to-cell or cell-to-ECM interactions that maintain the primary tumor mass; (2) penetrate local ECM and vessels; (3) exit the vessel and migrate into the extravascular space; and (4) survive and proliferate in foreign tissue [ 1 , 3 , 10 , 11 ].…”

“…Accordingly, MMP-9 expression level is believed to reliably monitor cancer clinical progression [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ].…”

“…Deregulated MMP-9 expression and/or activity causes cellular invasiveness and leads to the growth and clinical progression of a wide variety of human cancers [ 10 , 14 , 15 , 16 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ].…”

“…Therefore, at the tumor site, MMP-9 produced by cancer cells combines with that synthesized by normal inflammatory, immune, parenchymal or stromal cells; this leads to a dramatic rise of MMP-9 protein levels which is not paralleled by an increase in TIMP synthesis [ 11 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ].…”

The Labyrinth of Renal Cell Carcinoma

“…Original articles in this issue show interesting findings with potential clinical application. Examples of the science and research presented in this Special Issue include: the influence of VHL deletion in the expression of an unfavorable genetic pattern in CCRCC [22]; how a low dose of curcumin inhibits RCC's metastatic behavior [23]; the predictive value of the overexpression of EVI1 in CCRCC [24]; the poor outcome of ChRCC patients who lose CDKN1A mRNA and protein expression [25]; the identification of distinct signatures of CCRCC progression through in-depth mapping of urinary N-glycoproteome [26]; how a preclinical evaluation method may evaluate the response to targeted therapies in patients with RCC [27]; the RNA sequencing results obtained in two examples of collecting duct renal cell carcinoma, an aggressive rare variant of RCC [28]; how GSTO1*CC genotype predicts shorter survival in CCRCC male patients [29]; the importance of MTA2 as a biomarker of metastatic progression in RCC [30]; the metabolic reprograming in RCC [31]; the prognostic implications of pAMPK immunostaining and its association with SMAD protein expression in CCRCC [32]; the different amount of chromosomal losses in classic ChRCC compared with the eosinophilic subtype of this neoplasm [33]; the potential influence of circular RNAs in CCRCC prognosis [34]; the association of interleukins 4Rα and 13Rα1 with the progression of RCC [35]; the glutathione metabolism in PRCC [36]; how the profiling of primary and metastatic samples of CCRCC reveals a high homology of metastases with a specific subregion of the primary tumor [37]; the interrelationship between serum uric acid levels and RCC survival [38]; and the importance of ghrelin promoting RCC invasion [39].…”