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    • ADAM has two alternative splicing forms a

    2022-05-27

    ADAM12 has two alternative splicing forms, a membrane-anchored long form (ADAM12-L) and a secreted short form (ADAM12-S). Both the long and short forms have metalloproteinase, disintegrin, cysteine-rich, and epidermal growth factor-like domains and can shed pro-heparin binding-epidermal growth factor (HB-EGF) from the membrane and cleave insulin-like growth factor binding proteins (IGFBP)-3 and −5, which correlate with cell proliferation [21,22]. Moreover, ADAM12-L has a cytoplasmic domain, which has three SH3 Sorbitol that can interact with PACSIN3, Src, and Fish [[23], [24], [25]]. Here, we demonstrate that ADAM12-L is involved in focal adhesion turnover through enhancing FAK activation to promote ESCC cell invasion. Furthermore, we found that interaction with ECM led to the activation of FAK/JNK/c-Jun axis and hence increased the ADAM12-L transcription via c-Jun regulation. Thus, a positive feedback loop between ADAM12-L and FAK/c-Jun in ESCC is established which continuously amplify the tumor cell-stroma interaction signal at the cancer invasive edge, leading to a highly aggressive phenotype of the esophageal carcinomas.
    Materials and methods
    Results
    Discussion ESCC is a highly aggressive cancer due to its early local and distant metastasis as well as lymph nodes metastasis [2]. As invasion is the initiative and essential step of metastasis, genes regulating tumor invasion could be key drivers of metastasis. Therefore, we generated a subgroup of ESCC cells, EC9706-P4, by using tumor invasion selection model. Indeed, the genes we identified from EC9706-P4 cells were mostly related to tumor invasion, including LOXL2, ITGB4 and TIMP3 [[49], [50], [51]], etc, besides ADAM12. We then verified that ADAM12-L was overexpressed in esophageal cancer tissues, and significantly correlated with tumor invasion, lymph node metastasis and clinical stage (TNM). Our in vitro experiments showed that overexpression of ADAM12-L promoted ESCC cell invasion dramatically. Our in vivo experiments also revealed that the ESCC tumors with ADAM12-L overexpression exhibited a highly aggressive phenotype with lung metastasis. Previous studies have indicated that overexpressed ADAM12 is associated with cancer progression [[52], [53], [54]]. ADAM12 promotes mammary tumorigenesis in the polyoma virus middle T antigen (PyMT) mouse model of breast cancer [55,56]. Specifically, elevated ADAM12-L mRNA levels have been linked to poor outcomes in lung cancer [57]. Our in vitro experiments showed that overexpression of ADAM12-L promoted ESCC cell invasion dramatically. As ADAM12 belongs to the metalloproteinase family, it is important to evaluate whether ADAM12 promotes ESCC invasion through the metalloproteinase function. Our data demonstrate that the metalloproteinase catalytic activity is not required for ADAM12-L to promote ESCC cell invasion, which agrees with the reports that ADAM proteases can regulate cell migration by the noncatalytic functions [58]. Together our data suggest that ADAM12-L is a critical regulator of ESCC metastasis. Interaction between cancer cells and stroma has been revealed to be essential for cancer metastasis. The tumor microenvironments co-evolves along with cancer progression and thereafter facilitates cancer metastasis [4]. ECM, as one of the major component of stroma, plays a key role in promoting cancer metastasis. Focal adhesions serve as the mechanical linkages with the ECM that mediates the regulatory effects of a cell in response to ECM interaction [59]. Connection between focal adhesions and components of the ECM generally involves integrins, which subsequently transduces the excellular regulatory signal into cells and leads to the activation of signal cascades for cell growth, survival, and invasion [7]. Our studies suggest that FAK is critically required for ADAM12-L-promoted ESCC invasion. Furthermore, our experiments demonstrate that ADAM12-L participates in the focal adhesion by up-regulating Y397 phosphorylation of FAK. Y397 is an autophosphorylation site, and β integrins are known to interact with the FERM domain of FAK to regulate this autophosphorylation in response to excellular signals [60]. β1 and β3 integrin are molecules that are frequently involved in FAK Tyr397 autophosphorylation and interact with ADAM12 [40,62,63]. In addition, ADAM15 have been reported to enhance FAK phosphorylation upon genotoxic stress and its cytoplasmic tail specifically binds to the C terminus of FAK, but not the FERM domain or the catalytic domain [64]. We speculate that ADAM12-L interacts with FAK at the similar domain, but this needs further verification. Therefore, we hypothesize that ADAM12-L may promote FAK phosphorylation in an integrin dependent manner by enhancing the binding of β integrin with the FERM domain of FAK, therefore increasing the autophosphorylation of FAK, which may need further investigation.