The Role of Mir-21 and Mir-211 on MMP9 Regulation in Pancreatic Ductal Adenocarcinoma: Cooperation in Invasiveness Behaviors?

Keywords::

• PDAC
• miRNA
• miR-21
• miR-211
• MMP9
• invasion

Pancreatic ductal adenocarcinoma (PDAC) is a common cause of cancer death and has demonstrated bad prognosis in the last 10 years [1]. A large percentage of PDAC patients present with a locally advanced stage of disease (LAPDAC) and have a short median survival [2].

Surgical pathology behaviors, as well as tumor size and lymph node metastases, represent usual prognostic determinants in PDAC and are often common aspects in the pathological report [3]. The killer nature of this tumor has been associated with the power of its malignant cells to quickly metastasize regional, extra-regional lymph node, liver and lungs [4].

One of the major biological mechanisms regulating cell migration and tumor metastasis is the ‘epithelial–mesenchymal transition’ (EMT) process. EMT is a physiological process essential for transformation and cell migration in critical phases of biological development and affects the epithelial to mesenchymal phenotype transition. The activities of EMT deregulation drive tumor growth, progression and metastasis [5,6]. In more detail, EMT is activated by master molecules, including the TGF-β pathway, and in many cancers, including PDAC, EMT has been shown to be associated with tumor grading and metastatic processes [7]. Indeed, TGF-β seems to be a useful marker for PDAC patient outcome [8] and modulates several genes including MMPs.

The MMP activities and their TIMPS molecules play an important role in the degradation of connective tissue, which is associated with the development of tumor metastases in many cancers, including PDAC [8]. In particular, two of them, MMP-2 and MMP-9 (gelatinase A and gelatinase B) [9] are involved in the systemic dissemination of tumors. The importance of MMPs during tumor metastasis may be related to their proteolytic activity against type IV collagen, which is a major component of epithelial basement membranes [10].

Histological analysis showed a significant correlation among tumor levels of MMP-9 protein expression, positive lymph nodes and presence of distant metastases in PDAC [11]. The invasion and migration processes in PDAC were associated with high gene expression of EMT-associated factors as well as Slug, Snail, Twist and MMP-9 [12]. Furthermore, proteomic analyses showed a higher concentration of MMP9 protein in the pancreatic juice of PDAC patients compared with the cancer-free controls [12]. The MMPs and TIMPS in carcinomas have been showing a key role in the degradation of tumor microenvironement and tumor metastases formation [13]. Currently, at least 15 molecules are known to be involved, with different proteolytic activities to fight elements of the extracellular matrix. Regarding their enzymatic activities, MMPs have been categorized into five different groups: metalloelastases, collagenases, gelatinases, stromelysins and membrane-type MMP. In particular, MMP-2 and MMP-9 (gelatinase A and gelatinase B) are involved in tumor infiltration and migration, including in PDAC. The role of MMPs in tumor metastasis could be related to proteolytic activity against collagen, which represents the most important component of basement membranes [13]. The disruption of basal cellular membrane and its tissue infiltration by epithelial cancer cell makes the difference between adenocarcinoma and preneoplastic lesions.So far, the high levels of MMPs (especially MMP9) have been associated with infiltrating and metastatic processes, including in PDAC. MMPs activities are regulated through different genetic and epigenetic factors, as well as deregulation of mRNA transcription of growth factors, oncogenes and tumor suppressor genes. The mRNA stability and its translation seem to be another important mechanism involved in gene expression and protein generation, including MMPs. Indeed the role of microRNAs (miRNAs) and their differential expression in both tumor and normal cells play a pivotal role in cancer pathology, especially in growth, chemoresistance and, last but not least, in metastatic processes. A large part of the MMPs are produced as inactive proenzymes and need to become activated. Activation of MMP-2 requires a membrane-type 1 matrix metalloproteinase affecting the carboxy terminus of pro-MMP-2 [14]. Nevertheless, the active forms of MMPs are modulated by their TIMPs and the final result of MMP activity may be very difficult to define. Furthermore, high expressions of MMP-2, MMP-9 and their TIMPs have been found in pancreatic ductal adenocarcinoma [15]. However, looking at the whole context and comparing the new insights of basic science approaches, miRNAs disregulation seems to be the most important and appealing method of MMP regulation in PDAC. The analysis of different papers concerning miRNA expression in PDAC revealed the clinical relevance of two miRNAs (i.e., miR-21 and miR-211) in PDAC patients. These two micromolecules have been involved in some phenomena in pancreatic adenocarcinoma and in other different tumors. In particular, these two micromolecules have been associated with aggressiveness, progression and chemoresistance of PDAC [16–19]. Looking at data concerning chemoresistance of miRNAs cited above, they showed opposite effects with respect to gemcitabine metabolism in vitro. The upregulation of miR-21 was associated with increased IC50 of gemcitabine in PDAC cells; furthermore, high levels of miR-211 affected RRM2 expression in PDAC cells [18]. Overall, high levels of miR-21 and miR-211 were associated with shorter and longer overall survival of PDAC patients, respectively [17,18]. Indeed, one of them (miR-21) was associated with MMP2/9 modulation in primary tumor cell cultures of PDAC [17]. We have no evidence that miR-211 modulates MMP9 expression also, but some authors have demonstrated that the upregulation of miR-211 affected MMP9 expression in glioblastoma multiforme pathology [19]. On the whole, the differential expression of both miR-21 and miR-211 could be associated with invasiveness behavior in PDAC cells featuring MMP9 modulations. However, further investigation using immunohistochemistry and western blot analyses are needed to detect the relative ratio between total amount of active and inactive MMP9 proteins.

Financial & competing interests disclosure

Funding from Istituto Toscano Tumori (ITT). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

Funding from Istituto Toscano Tumori (ITT). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.