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    • The Rho family of GTPases is composed of many small

    2022-06-21

    The Rho family of GTPases is composed of many small ubiquitous signaling G proteins that bind to guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). They act as switches: when binding to GTP, they are active and associate with a variety of target proteins that regulate intracellular Abiraterone dynamics needed for cell movement. Canonical members of Rho family include RhoA, Rac1, and Cdc42[16], [36]. As adherence junction processes including formation, stability, and dissolution are regulated by Rho family GTPases and deletion of FAK in mice destabilizes RhoA and Rac1 activities, activated RhoA was tested in ESCC and RhoA activation was found to change accordingly with MME overexpression or knock-down in ESCC tumor cells. F-actin was also influenced as anticipated because actin cytoskeleton is a major target of Rho GTPases, which serve as a molecular switch on a variety of signaling pathways. Downstream MEK/ERK activation that is involved in tumor metastasis was also inhibited by MME overexpression.
    Acknowledgement
    Introduction Human esophageal carcinoma is the sixth leading cause of cancer death worldwide, which occurs with particularly high frequency in China [1,2]. Esophageal squamous cell carcinomas (ESCCs) is the major type of esophageal cancer in China, which have a poor prognosis frequently due to early metastasis to the lymph nodes and the neighbor organs such as aorta, trachea, and lungs [2]. However, the underlying mechanism of metastasis in this disease is largely unknown. Metastasis is a multistage process which are initiated and continuously driven by the interaction of tumor cells with the microenvironment [3]. Then the metastatic signal from stroma to tumor cell surface and the further cascade into nucleus initiate gene transcription that promotes metastasis. During the course of cancer progression, continuous tumor-stroma interactions also contribute to the evolvement of microenvironment to an activated state, which has been delineated as one the hallmarks of cancer [4]. Invasion of cancer is not simply the process that degrades the extracellular matrix (ECM) to create the tracks for cancer cell to go through, but also involves the communication of ECM with cancer cells to activate their metastatic signals. Focal adhesions (also cell–matrix adhesions or FAs) are the structures that play a central role in facilitating interaction of cells with the ECM [5,6]. Focal adhesions function as important signaling centers, through which integrins transduce signals from the ECM to regulate cell growth, survival, and invasion [7]. Focal adhesion kinase (FAK) locates in focal adhesions and plays critical roles in integrin-mediated signal transductions and also participates in signaling by other cell surface receptors [8]. Turnover of focal adhesions is an essential step of the dynamic and multistep process of cancer cell metastasis [9,10]. Hyper-activation of FAK has been found in various human cancers [[11], [12], [13]]. Active FAK promotes cancer cell migration via several downstream signaling pathways, such as Src, PI3K, N-WASP mediated pathways [8]. To explore the genes that are involved in the early event of esophageal cancer metastasis, we established a highly metastatic sub-line from EC9706, an esophageal squamous cancer cell line [14], using an in vitro selection model to mimic the interaction of tumor cells with ECM. Genome-wide microarray analysis revealed that ADAM12 was overexpressed in the highly metastatic sub-line when compared to the parental cells. ADAM12 belongs to the ADAMs family (a disintegrin and metalloprotease), a family of transmembrane and secreted metalloendopeptidases comprised of approx 40 members [15,16]. ADAMs are characterized with a metalloprotease, a disintegrin, a cysteine-rich, an epidermal-growth factor like and a transmembrane domain, as well as a C-terminal cytoplasmic tail [17]. The metalloprotease domain of ADAMs can cut off or shed extracellular portions of transmembrane proteins [18]. For example, HER2 receptor can be cut off by ADAM10 and then be activated [19]. Nonetheless, some of ADAMs lack the protease domain, indicating that their function may depend on protein–protein interactions [18,20].