ADAM28 plays important roles in regulating cell proliferation, apoptosis, migration and invasion and in angiogenesis in malignant tumors. Elevated expression of ADAM28 has been found in leukemia and lung cancer, breast cancer, and digestive tract tumors, and overexpression of the ADAM28 gene is closely related to poor outcomes in patients with tumors. ADAM28 is known to be involved mainly in regulating tumor progression by acting on substrates such as IGFBP-3, vWF, and CTGF (Fig. 2).

Fig. 2

Functional roles of ADAM28 in cancer cell proliferation, invasion and metastasis. A ADAM28 reactivates IGF-1 by cleaving IGFBP-3 in the IGF-1/IGFBP-3 complex, stimulate cell proliferation. B ADAM28 selectively degrades CTGF in the complex of CTGF and vascular endothelial growth factor, thereby releasing biologically active VEGF and promoting the formation of tumor angiogenesis. C ADAM28 may play an invasive role through SOX4-mediated EMT. D The catalytic site in the metalloproteinase domain of ADAM has a high degree of sequence homology with MMPs. ADAM28 promotes invasion by degrading ECM components. E ADAM28 can promote P-selectin/glycoprotein ligand complex (PSGL-1/P-selectin)-mediated tumor cell rolling adhesion to endothelial cells and subsequent transendothelial migration into the interstitial space. F ADAM28 can cleave vWF, leading to protein degradation of vWF in the human body and inhibiting its effect of promoting cell apoptosis

3.1 ADAM28 promotes cell proliferation

ADAM28 promotes cell proliferation by cleaving IGFBP-3. IGFBPs are a class of proteins that bind two types of insulin-like growth factors (IGFs). IGFBP-3 is the most abundant and main carrier of IGF-1 in blood plasma and forms a high-molecular-weight complex with an acid-labile subunit (ALS) in the blood circulation. Since this complex cannot exit the blood vessels and prevents IGF-1 from interacting with its receptor, the binding of IGFBP-3 to IGF-1 in the plasma reduces IGF-1 bioavailability [11].

ADAM proteases can regulate cancer cell proliferation through growth factors and the shedding of the extracellular domains of ADAM protease receptors. ProADAM28 is activated by MMP-7, after which its metalloproteinase bond between Arg97 and Ala98 is responsible for IGFBP-3 cleavage, which causes IGFBP-3 to dissociate from the IGF-1/IGFBP-3 complex, thereby reactivating IGF-1. The activation of insulin-like growth factor receptor (IGFR) initiates an intracellular signaling cascade via phosphorylation of the downstream molecule ERK1/2, which promotes cell proliferation [5, 8]. Furthermore, IGF-1 is reported to bind to the insulin-like growth factor 1 receptor (IGF-1R), activating downstream PI3K/AKT/mTOR and RAS/MAPK pathways and promoting tumor cell proliferation, survival and chemoresistance [5].

ADAM28 plays a role in the proliferation of lung cancer, breast cancer and malignant blood cancer cells. Many studies have shown that ADAM28 is closely related to the occurrence, development and drug resistance of non-small cell lung carcinomas (NSCLCs) and asbestos-related lung cancer (ARLC). Ohtsuka et al. first indicated that ADAM28 is overexpressed and activated in human NSCLC and that the expression level of ADAM28 is correlated with tumor size, the presence or absence of lymph node metastasis, and the MIB1-positive cell index in cancer tissue, suggesting that ADAM28 may participate in human lung cancer cell proliferation and progression. In early-stage lung cancer, the expression level of ADAM28 is low, but as the tumor progresses to the advanced and metastatic stages, the expression of ADAM28 significantly increases, suggesting that it may play a key role in the invasion and metastasis of lung cancer. This conclusion was confirmed in subsequent studies, in which the overexpression of ADAM28 in human lung cancer cells and the mRNA expression level of ADAM28 were directly related to the proliferative activity of cancer cells and lymph node metastasis [12].

The catalytic site in the metalloproteinase domain of ADAMs has high sequence homology with MMPs. MMPs play important roles in the development and progression of various human cancers, including breast cancer, by degrading extracellular matrix components such as basement membrane components [13]. Therefore, the expression and activation status of ADAMs may be similar those of MMPs in breast cancer tissue and may be involved in the occurrence, invasion and metastasis of breast cancer [6]. Mitsui et al. evaluated the expression of 12 different ADAM metalloproteinase types and reported that ADAM28 was overexpressed in human invasive breast cancer tissue and was associated with cancer cell proliferation. ADAM28 is highly expressed in invasive breast cancer, especially in triple-negative breast cancer (TNBC). In advanced and metastatic breast cancer, ADAM28 expression also tends to increase significantly, suggesting that it may play an important role in breast cancer metastasis. ADAM28 expression is associated with the proliferative index of the tumor and a poor prognosis for patients. With respect to the molecular mechanism of ADAM28 gene expression in cancer cells, it has been reported that the nonreceptor tyrosine kinase Src induces ADAM28 expression in human cancer cells via the PI3K/AKT/mTOR and MEK/ERK pathways [14].

The expression level of ADAM28 is increased in patients with de novo acute myeloid leukemia (AML) and patients with AML relapse, and ADAM28 expression differs significantly between patients with relapse and patients in complete remission. In addition, the level of ADAM28 in the cerebrospinal fluid of patients with central nervous system leukemia (CNSL) is significantly greater than that in patients without CNSL. Moreover, the cumulative incidence of relapse (CIR) in patients with high ADAM28 expression is significantly greater. The expression level of ADAM28 is negatively correlated with patients’ relapse-free and event-free survival. Studies have shown that ADAM28 promotes the growth and spread of AML by selectively cleaving the IGF-I released from the IGF-I/IGFBP-3 complex, which induces cell proliferation, and plays a key role in regulating the proliferation and invasion of leukemia cells and predicting relapse in AML patients [15].

MicroRNAs (miRNAs) play crucial roles in the progression of human colorectal cancer (CRC). miR-552 can act as an oncogene in CRC and promote cancer metastasis by directly targeting ADAM28 in CRC cells [16]. miR-198 is a tumor-suppressive miRNA, and its expression in CRC cells is significantly lower than that in the normal colon cell line FHC. The overexpression of miR-198 inhibits the proliferation and colony formation of CRC cells and promotes their apoptosis. Further studies revealed that ADAM28 is a direct target of miR-198 and that overexpression of ADAM28 can reverse the effects of miR-198 on tumor cell behavior [17]. In addition, the 3′ untranslated region (3′-UTR) of ADAM28 binds to miR-574-3p, which can reduce the expression of ADAM28 in hepatocellular carcinoma cells and inhibit their growth, indicating that miR-574-3p targets ADAM28 and negatively regulates its expression [18].

3.2 ADAM28 resists apoptosis

Vascular endothelial growth factor (VEGF) is a key factor in the blood coagulation process. In addition, vWF is involved in pathophysiological processes such as angiogenesis, cell proliferation, inflammation and tumor maintenance [13]. Under normal circumstances, vWF is expressed only in endothelial cells and megakaryocytes in the body. Studies have shown that vWF is also expressed in some tumor cells of nonendothelial origin and is involved in tumor initiation and development [14]. Moreov er, ADAM28 has been shown to cleave the protein vWF via the A1 domain, leading its degradation in the human body and inhibiting its role in promoting apoptosis.

Cells with low ADAM28 expression (such as MCF-7, 769P and HepG2 cells) are sensitive to vWF-induced apoptosis, whereas cells with high ADAM28 expression (such as PC-9, CALU-3, MDA-MB231 and Caki-2 cells) are resistant to vWF-induced apoptosis [15]. Wright et al. identified the ADAM28 gene as the most relevant among six candidate genes (ZNRF3, ADAM28, PPP1CA, IRF6, RAB3D and PRDX1) associated with the carcinogenicity of asbestos as a potential biomarker for asbestos-related cancer [16]. In 2012, Mochizuki et al. reported that ADAM28 cleaves proapoptotic vWF in cancer cells, promoting lung metastasis by inhibiting the apoptosis of intravascular cancer cells [15]. In addition, studies have shown that ADAM28 is upregulated in gastric cancer cells. In particular, the expression of ADAM28 is significantly increased in advanced and metastatic gastric cancer, suggesting that it may play an important role in the invasion and metastasis of gastric cancer, and that its overexpression/knockdown in gastric cancer cells regulates the proliferation, apoptosis and migration of these cells. Specifically, ADAM28 in gastric cancer cells cleaves vWF to eliminate vWF-induced apoptosis. Knockdown of vWF counteracted the effects of knocking down ADAM28, which led to increases in integrin β3, p-TP53 and c-Casp3 expression levels. Therefore, ADAM28 may play a role in promoting metastasis by cleaving vWF and inhibiting vWF-induced apoptosis in gastric cancer cells [17]. However, after verification at the transcription level and survival analysis of Helicobacter pylori-associated gastric cancer and normal tissues, ADAM28 was ruled out as a key gene in the development of gastric cancers related to H. pylori infection [18]. In addition, nuclear paraspeckle assembly transcript 1 (NEAT1) is overexpressed in various cancers, such as gliomas, CRC, leukemia and NSCLC, and negatively regulates miR-128-3p. Downregulation of miR-128-3p further leads to an increase in ADAM 28 expression, which in turn induces the activation of the JAK 2/STAT 3 signaling pathway, ultimately promoting autophagy and inhibiting apoptosis in NSCLC cells [19].

3.3 ADAM28 promotes epithelial–mesenchymal transition (EMT)

Studies have shown that P-selectin glycoprotein ligand-1 (PSGL-1) binds to ADAM28 to promote the rolling adhesion of human promyelocytic leukemia cells to endothelial cells and the subsequent transendothelial migration to the interstitial space mediated by the P-selectin/glycoprotein ligand complex (PSGL-1/P-selectin). These findings suggest that ADAM28 may be involved in the proliferation and metastasis of human lung cancer cells by regulating the tumor microenvironment and cell adhesion [20]. Notably, another study showed that selective inhibition of ADAM28 can inhibit the growth and metastasis of lung cancer cells [21]. In 2018, Sasaki et al. reported that SRY-related HMG-box 4 (SOX4) is an inducer of EMT and a transcriptional activator of the ADAM28 gene. SOX4 transactivates the expression of the ADAM28 gene by directly binding to the ADAM28 promoter region, suggesting that ADAM28 may play a role in the invasion of human breast and lung cancer via SOX4-mediated EMT [22].

CTGF is a substrate of ADAM28. Studies have shown that CTGF plays important roles in tumorigenesis and tumor progression by promoting cancer cell proliferation, migration, invasion, metastasis and EMT [23]. In 2010, Mochizuki et al. demonstrated that CTGF binds to ProADAM28 and that ADAM28 cleaves the bonds between Ala181 and Tyr182 and between Asp191 and Pro192, which leads to the degradation of CTGF in the CTGF-VEGF165 complex, thereby releasing the biologically active VEGF165 and it is an isoform of vascular endothelial growth factor that can stimulate the proliferation and migration of endothelial cells and promote the formation of new blood vessels in tumors [24].

3.4 ADAM28 and immune-related factors

ADAM28 was first found in lymphocytes, indicating that it may play a role in the immune system and participate in biological processes such as cell adhesion, cell fusion, membrane protein shedding and protein hydrolysis [4, 25,26,27]. CD200 is a membrane glycoprotein in the immunoglobulin superfamily that plays immunosuppressive roles in autoimmune diseases, fetal rejection, and transplant tolerance [28]. CD200 is overexpressed in some malignant hematological tumors and is associated with disease progression and prognosis in lymphoma and leukemia [29]. ADAM28 affects the immune escape of tumor cells by regulating the shedding of CD200. CD200 is an immunosuppressive molecule that inhibits the activity of immune cells and promotes the immune escape of tumor cells. In chronic lymphocytic leukemia (CLL), ADAM28 mRNA expression is correlated with plasma sCD200 levels and CLL cell release in culture. The overexpression or knockdown of ADAM28 in CD200+ cells results in a corresponding increase or decrease in sCD200 release, respectively. A study suggested that the shedding of CD200 from the extracellular domain of the B-CLL cell surface is regulated by ADAM28 expression. In addition to the clinical utility of novel CLL therapies that block CD200 expression/function, the release of sCD200 can also be targeted by inhibiting the expression/function of ADAM28 [30].

ADAM28 promotes the shedding of tumor necrosis factor-α (TNF-α) from the cell surface. In addition to its roles in the maintenance and homeostasis of the immune system, inflammation and host defense, TNF-α is also involved in pathological processes such as chronic inflammation, autoimmunity and cancer [31]. When TNF-α was first discovered in 1975, it was noted to induce hemorrhagic necrosis in tumors. TNF-α is therefore considered one of the most promising anticancer cytokines [32]. Surprisingly, when TNF-α is produced in the body by host cells surrounding tumors, it does not have anticancer properties but rather promotes inflammation and tumor growth. Therefore, TNF-α has a dual role in cancer, as it can either enhance or inhibit tumor progression depending on its specific cellular environment [33]. Studies have shown that when ADAM28 and TNF-α are overexpressed in HEK 293 cells, TNF-α shedding increases, but when ADAM28 downregulated or its activity is inhibited, shedding is significantly reduced [34].

3.5 ADAM28 is associated with drug resistance

Surgery combined with chemotherapy is the combination treatment of choice for most patients with malignant tumors. However, some patients inevitably develop resistance to chemotherapy, which increases the risks of tumor recurrence and metastasis. Chemotherapy resistance h during treatment as become an urgent problem that needs to be solved [35].

Studies have shown that ADAM28 is related not only to the proliferation, metastasis and invasion of tumor cells but also to chemoresistance in NSCLC and pancreatic cancer cells. Circular RNAs (circRNAs) are a class of highly stable RNA molecules with loop structures closed by the formation of covalent bonds. CircRNAs are associated with the cell cycle and the growth, differentiation, apoptosis, metastasis and cisplatin sensitivity of tumors [36]. CircRNA_100565 is upregulated in cisplatin (DDP)-resistant NSCLC cells, and such high expression is associated with a shortened overall patient survival [37]. The 3′-UTR of ADAM28 or CircRNA_100565 can directly bind to miR-377-3p. Deletion of CircRNA_100565 can reduce DDP resistance, inhibit the proliferation and autophagy of DDP-resistant NSCLC cells, reduce the IC50 value of DDP, and increase apoptosis. In NSCLC cells, ADAM28 expression is indirectly regulated by circRNA_100565 via miR-377-3p. The expression of ADAM28 or the inhibition of miR377-3p can significantly reduce the DDP sensitivity of resistant NSCLC cells induced by the loss of CircRNA_100565 [37]. Research has shown that the mRNA and protein levels of ADAM28 are elevated in gemcitabine-resistant pancreatic cancer cells and that gemcitabine can induce ADAM28 expression. ADAM28 may induce gemcitabine resistance in multiple ways. On the one hand, ADAM28 may affect the expression or function of gemcitabine transporters. Gemcitabine needs to enter cells through human nucleoside transporters (NTs) to exert its effects. ADAM28 may downregulate the expression of NTs, reduce the entry of gemcitabine into cells, and thus lead to resistance. On the other hand, ADAM28 may participate in the regulation of the tumor microenvironment, interact with tumor-associated fibroblasts (CAFs), and promote pancreatic cancer cells’ resistance to gemcitabine through pathways such as paracrine cytokines [10]. These findings provide important ideas for the discovery of new targets for the treatment of pancreatic cancer.

In addition, ADAM28 promotes cell survival and inhibits apoptosis by cleaving IGFBP3, releasing free IGF-1 and activating the PI3K/Akt/mTOR and Ras/MAPK pathways [6, 38]. ADAM28 binds to multiple integrins (such as α4β1, α4β7, and α9β1) through its disintegrin domain, promoting cell adhesion and migration. This effect may help tumor cells spread in the body, thereby enhancing their tolerance to treatment. ADAM28 has the activity of degrading extracellular matrix components such as glycosaminoglycans. This matrix remodeling ability may change the tumor microenvironment and provide tumor cells with conditions that are more conducive to growth and drug resistance[8].