Prognostic Values for the mRNA Expression of the ADAMTS Family of Genes in Gastric Cancer

Abstract

The “A Disintegrin and Metalloproteinase with Thrombospondin Motif” (ADAMTS) family of genes is involved in the occurrence and development of different cancers. However, the prognostic value of these genes in gastric cancer (GC) has not been revealed. The present study was thus conducted to determine the prognostic value for the ADAMTS family of genes in GC. First, we evaluated the mRNA expression levels of the ADAMTS family in GC patients using a GEPIA dataset. Thereafter, we determined the prognostic value of these genes by analyzing their mRNA level using the Kaplan–Meier Plotter database. The mRNA expression level of ADAMTS12 was randomly validated by qRT-PCR and meta-analysis while its coexpression genes were derived using Coexpedia. Finally, we performed Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses using the OmicShare Tools. Compared to normal tissues, expression of ADAMTS2 and 12 was significantly higher while that of ADAMTS1, 13, and 15 was significantly lower in GC tissues. According to the RNA-seq and gene chip data, the ADAMTS family (6, 7, 12, 15, and 18) of genes was closely related to the prognosis of GC, and their high expression levels were associated with poor prognosis and survival time. In addition, ADAMTS12 was highly expressed in 20 pairs of GC tissues based on RT-PCR (P=0.016) and meta-analysis (SMD: 0.73, 95% CI: 0.32–1.14, P<0.001). GO and KEGG pathway analyses indicated that the ADAMTS12 coexpressed genes were enriched in the pathways of extracellular matrix organization, extracellular matrix structural constituent, extracellular matrix, and protein digestion and absorption. Herein, we discovered the prognostic values and biological roles of the ADAMTS genes in GC.

ADAMTS-12: Functions and Challenges for a Complex Metalloprotease

“…Furthermore, in support of previous observations, by different genomic approximations the ADAMTS-12 locus has been associated with several human pathologies like asthma, schizophrenia or predisposition to pediatric stroke (Kurz et al, 2006;Arning et al, 2012;Bespalova et al, 2012). In recent years, genome-wide and bioinformatics analysis techniques have been used with results supporting ADAMTS12 participation in those pathological processes and also in new situations with the benefit of the possibility of being used as a prognosis biomarker (Hu et al, 2020;Liang et al, 2020;Zhang et al, 2020). However, besides its participation in pathological situations much more research is needed to identify ADAMTS-12 interacting partners and its substrates in normal or pathological processes.…”

“…However, when ADAMTS-12 interacts with fibulin-2, these effects are reversed, promoting an antitumor role (Fontanil et al, 2014). Other studies seem to suggest the tumorigenic function of this protein since the gene encoding for ADAMTS12 has been identified as one of the genes overexpressed in ovarian cancer patients with intestinal metastases (Mariani et al, 2019), in patients with metastatic renal carcinoma (Ho et al, 2017), gastric carcinoma with poor prognosis (Liang et al, 2020) and esophageal squamous cell carcinoma (Li et al, 2020b).…”

“…In breast cancer, ADAMTS-12 expression is localized preferentially surrounding the tumoral tissue and high expression is correlated with good prognosis of these patients (Fontanil et al, 2014). On the other hand, expression analysis in gastric cancer has revealed high levels of ADAMTS-12 in tumoral samples when compared to adjacent tissue and a correlation with poor prognosis (Liang et al, 2020). In this sense, the availability of gene expression databanks can be a great tool to analyze gene participation in cancer.…”

“…ADAMTS12 expression was detected in a variety of tissues like cartilage, lung, kidney, liver, synovium, tendon, skeletal muscle, adipose (Liu, 2009;El Hour et al, 2010;Moncada-Pazos et al, 2012). It is also widely expressed in tumors from different origins and mainly associated with the gastrointestinal tract, suggesting that this enzyme could also participate in the development or progression of this type of tumors (Liu et al, 2006b;Moncada-Pazos et al, 2009;Wang et al, 2011;Fontanil et al, 2014;Liang et al, 2020;Rabadan et al, 2020).…”

The Tumor Proteolytic Landscape: A Challenging Frontier in Cancer Diagnosis and Therapy

“…They are generally divided into the group of hyalectanases, including ADAMTS-1, -4, -5, -8, -9, -15, and -20, which mostly target various (hyalectan) proteoglycans, ADAMTS-2, -3 and -14 which process the N-terminal propeptides of collagens, and the remaining group of ADAMTS-6, -7, -10, -12, -13 and -16, which have more specific functions [ 106 , 107 , 108 ]. Accumulating evidence suggests several ADAMTSs are involved in cancer development and progression and can promote tumor development [ 49 , 50 , 51 ], but their roles in proteoglycan proteolysis also have tumor suppressor functions [ 109 ] and their prognostic value was evaluated in the context of different cancers [ 110 , 111 , 112 ]. Since the involvement of different members of the metalloproteinase families has been reported in nearly all known forms of cancer, they are considered one of the most important target protease groups in cancer research.…”