miRNA/ADAM Protein Axes in Gastrointestinal Cancers: History
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Contributor:
Agnieszka Kalita
,
Magdalena Sikora-Skrabaka
,
Ewa Nowakowska-Zajdel

Gastrointestinal (GI) cancers are some of the most common cancers in the world and their number is increasing. Their etiology and pathogenesis are still unclear. ADAM proteins are a family of transmembrane and secreted metalloproteinases that play a role in cancerogenesis, metastasis and neoangiogenesis. MicroRNAs are small single-stranded non-coding RNAs that take part in the post-transcriptional regulation of gene expression. Some ADAM proteins can be targets for microRNAs.

  • gastrointestinal cancers
  • microRNA/miR
  • ADAM proteins

1. Introduction

Gastrointestinal (GI) cancers are some of the most common cancers in the world. GI cancers include malignancies of the GI tract (esophagus, stomach, small intestine, colon, rectum and anus) and other digestive organs (pancreas, gallbladder, liver and bile ducts) [1]. According to the International Agency for Research on Cancer’s estimation, there were about 5.1 million new GI cancer cases and over 3.5 million GI cancer deaths in the world in 2020 [2]. The etiology and pathogenesis of GI cancers are multifactorial, but despite many studies worldwide, they are still unclear [3]. One of the research directions is looking into the role of ADAM proteins and microRNAs in cancer development and progression, and options for treatment as well as drug resistance.
ADAMs are a family of transmembrane and secreted metalloproteinases that play an important role in cancerogenesis, metastasis and neoangiogenesis. They have the potential to be used as prediction biomarkers or pharmaceutical targets. The role of ADAM 8, 9, 12, 17, 29 and 33 is best known in GI cancers [4][5]. ADAMs’ role in carcinogenesis is associated with chronic inflammation processes. For example, the molecular targets of ADAM10 and ADAM17 in inflammation and cancer are tumor necrosis factor-alfa (TNF alfa), inteleukin-6 (IL-6), ICAM-1 and epidermal growth factor (EGF) [6][7][8]. ADAM28 can reactivate the activity of insulin growth factors (IGFs) in the complex of insulin growth factor binding protein-3 (IGFBP-3). IGF signaling leads to proliferation in different GI cancers [9]. Numerous studies also showed that ADAM expression is associated with poor prognosis in cancer patients [10][11]. Proteins of the ADAM family (ADAMs and ADAM with trombospodin motif—ADAMTS) play critical roles in cell–cell and cell–extracellular matrix (ECM) communication. ADAMs are membrane proteins characterized by additional EGF-like, transmembrane and cytoplasmic domains, and ADAMTSs are proteins secreted by cancer and stromal cells, characterized by an ancilliary domain containing trombospodin. ADAMTSs may contribute to modifying tumor microenvironments and are implicated in cell invasion, migration, proliferation and angiogenesis via mechanisms involved in cleaving or interacting with ECM components or regulatory factors [12]. ADAMs and ADAMTSs have catalytic properties. Most of their substrates are membrane-bound precursors. Only 12 ADAMs, including ADAM 8, 9, 10, 12, 15, 17, 20, 21, 28, 30 and 33, have a catalytic site, and two of them (ADAM 20 and 21) have no known substrates. The substrates for the ADAMs are growth factors, chemokines, adhesion molecules and their receptors [13]. Among these ADAMs, ADAM8, 9, 10, 12, 15, 17, 19, 22, 23 and 28 have been demonstrated to play a regulatory role in the initiation, procession and metastasis of cancers [14].
In recent years, microRNAs (miRs) have been of great interest, and there are a few emerging studies on miRs and ADAMs in cancer. MiRs belong to the RNA interference family, originally discovered in 1998 by Andrew Fire and Craig Mello (2006 Nobel Prize laureates in Physiology or Medicine) [15]. About 2600 miRs have been identified in the human genome [16]. They are small single-stranded non-coding RNAs that take part in the post-transcriptional regulation of gene expression. MiRs play a fundamental role in the regulation of physiological processes such as embryogenesis as well as several human pathologies such as cancer, and auto-immune and cardiovascular diseases [17][18][19]. MiRs can be released into bodily fluids such as stools and blood [20][21]. They play roles in cancer biology, such as cell cycle control, metabolism, apoptosis, metastasis and angiogenesis. MiRNAs have also been introduced as promising therapeutic targets for cancer treatment [22].

2. ESCC and miR-126/ADAM9

Liu et al. found that miR–126 overexpression in tumor tissue suppressed ESCC development and progression by inhibiting the activation of the ADAM9–EGFR–AKT pathway. This study confirmed that ADAM9 functions as a direct target of miR-126 and contributed to miR-126 repressing cell migration in ESCC [23]. The most important goal of this research was to prove that the regulation of some ADAM/miR axes may have therapeutic potential in the treatment of ESCC.

3. GC and miR-126, miR-129-5p/ADAM9, miR-338-3p/ADAM17, miR-320a/ADAM10

Based on scientific reports, the correlation between miRNA and ADAMs seems to be a strong factor in GC development. In a study carried out by Wang et al., ADAM9 was overexpressed in GC tissues, and its high levels were significantly correlated with more advanced GC clinicopathological features, such as local advancement and metastasis, described in the TNM system. MiR-126 was downregulated in GC cells. The results of this study suggest that ADAM9 is one of the targets regulated by miR-126 in GC cells and in this process, miR-126 performs its potential tumor suppressive function in GC [24][25].
Liu et al. found that miR-129-5p functions as a tumor suppressor in GC progression, also via targeting ADAM9. Their study showed that the levels of miR -129-5p are lower in GC tissues and cell lines than in cancer-free controls, which can be associated with poor prognosis of GC patients [26]. In their study, Chen et al. demonstrated that miR-338-3p level is significantly decreased both in GC tissues and cell lines and its progression is partially inhibited via the downregulation of ADAM17. This metalloproteinase regulates the release of TNF-α and ligands of EGFR from cells. ADAM17 was identified as a direct target of miR-338-3p [27]. The miR-338–3p/ADAM17 axis is also regulated by circular RNA circ_0051620, the overexpression of which is associated with GC metastasis and poor prognosis [28]. Ge et al. reported that the overexpression of ADAM10 and decreased level of miR-320a in GC cell lines. Their investigation indicates that 3′-UTR of ADAM10 is the target of miR-320a. The aim of their work was also to study the influence of the miR-320a/ADAM10 axis regulation on the sensitivity of GC cells to cisplatin. They proved that miR-320a overexpression in GC cells increases their sensitivity to cisplatin. Their findings suggest that ADAM10 is a functional target of miR-320a in GC development and chemoresistance [29].
These presented studies revealed that increased miR-126, miR-129-5p, miR-320a and miR-338-3p suppressed GC cell proliferation via the regulation of ADAM-dependent pathways, which indicates that they may be a potential target for GC therapeutic treatment.

4. PC and miR-126/ADAM9, miR-328/ADAM8

PC is one of the deadliest cancers in the world. The etiopathogenesis is still unclear despite many investigations worldwide. Currently, surgical resection is the only option for a cure, but over 75% of PC cases are unresectable at the time of diagnosis [30]. This is why we very much need diagnostic and treatment options that may improve overall survival in patients suffering from PC.
In PC cell lines, MiR-126 functions as a tumor suppressor via the regulation of ADAM9, which was confirmed by Hamada et al. The miR-126/ADAM9 axis plays a role in cellular migration, angiogenesis and invasion of PC cells, which is crucial in metastasizing [31]. Yu et al. found that propofol suppressed the development of PC cell lines through the downregulation of ADAM8 via the overexpression of miR-328. In this study, the ADAM8/miR-328 axis was identified as a novel pathway of PC progress. The overexpression of ADAM8 was found in some GI cancers such as pancreatic, colon or gastric cancers and was a negative prognostic factor. This study suggests that propofol may be one of the PC treatment options in the future [32]. The miR/ADAM axis is a promising direction in research on PC development, treatment and diagnosis. The presented studies seem to indicate new potential options for treatment.

5. HCC and miR-122, 145, 3136/ADAM17, miR-203, 1274-a/ADAM9

HCC is the primary liver cancer and is closely related to chronic viral hepatitis caused by the hepatitis B or C virus. It is also associated with excessive alcohol use and other chronic liver diseases that lead to cirrhosis. Despite commonly known risk factors, the prognosis is poor because of late diagnosis of HCC worldwide [33]. ADAM17 is overexpressed in many cancers. Investigators identified ADAM17 as a target for miR-122, 145 and 3163. Wei-Chih Tsai et al. found that miR-122 is suspected to be a tumor suppressor because its level is downregulated in HCC tissues and cell lines, just as in GC cells. The restoration of miR-122 via the downregulation of ADAM17 caused a reduction in tumorigenesis, angiogenesis and invasion [34]. Yuwu Liu et al. found that miR-145 and 224 expression is higher in HCC tissue than in normal liver cells. They investigated whether or not there is a connection with the overexpression of ADAM17. However, the correlation was not confirmed. ADAM17 is not the target for miR-145 and 224 [35]. In contrast to their previous study, they found that miR-145 is downregulated in HCC and is considered as a tumor suppressor activated via ADAM17 [36]. This is why miR-122 and 145 can be potentially curative, although the role of miR-145 is still unclear. Further research is necessary. Additionally, it has been well established that miR-122 reduces chemoresistance [37].
ADAM9, which is connected to tumor cell proliferation, invasion and inhibition of apoptosis, is also upregulated in HCC cells. MiR-203 can be described as a tumor suppressor through downregulating ADAM9 [38]. The miR-126/ADAM9 axis is described in HCC and is connected with cancer progression. Moreover, Le-yang Xiang et al. found that miR-126 is downregulated in HBV-related HCC patients without pre-operational treatment, which causes tumor development and progression by targeting ADAM9 [39].
Bin Yang et al. found that the MiR-3163/ADAM17 axis regulates the Notch pathway, which takes part in the sensitivity of HCC cells to targeted molecular treatment, such as sorafenib, and they suggest that miR-3163 can enhance this sensitivity [40]. MiR-1274-a is upregulated in HepG2 cells after sorafenib treatment, while ADAM9 is downregulated and its expression can be also suppressed by miR-1274-a [41]. These studies show other therapeutic potential for miRs.

6. CRC and miR-30c/ADAM19, miR-198/ADAM28, miR-20b/ADAM9

Both ADAMs and miRs have been intensively researched in the context of the pathogenesis of CRC, but the correlation between them is still poorly known. Wang J et al. found that the expression of miR-552 and miR-592 is upregulated in tumor tissues and cell lines and correlates with the advancement of the disease described by TNM. They also proved that miR-552 additionally promotes CRC metastasis by targeting ADAM 28 [42]. ADAM19 is upregulated in renal cell carcinoma and primary brain tumors and plays a role in the pathogenesis of various diseases, such as chronic obstructive pulmonary disease [43][44]. MiR-30c was identified as a tumor growth, migration and invasion suppressor targeting ADAM19, which is also overexpressed in CRC tissues. However, this study shows that ADAM19 is not the only target for miR-30c because the cancer development rate was greater than the reduction in ADAM19. MiR-30c is suggested to be one of the therapeutic possibilities in CRC therapy [45]. The JAK/STAT pathway promotes the progression of cancers through, for example, cell proliferation, invasion and migration. In a study carried out by L.-X. Li et al., it was shown that miR-198 inhibits CRC progression by regulating the ADAM28/JAK-STAT signaling pathway. MiR-198 is detected as a tumor suppressor [46]. MiR-20b is downregulated in colon tumor tissue versus normal tissue. In their study, Qiang Fu et al. studied the mechanism of chemoresistance to 5-FU in colon cancer. 5-FU is the standard component of chemotherapy in CRC and improves the overall survival of patients with CRC. They found that miR-20b can reduce 5-FU resistance by inhibiting the ADAM9/EGFR pathway. This result indicates that miR-20 can be a promising direction of future studies and therapy [47][48]. These studies show that some miRs can be used as prognostic or predictive factors and, in correlation with adamalisines, can play a role in CRC treatment.

This entry is adapted from the peer-reviewed paper 10.3390/cimb45040191

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