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    • The membrane metalloendopeptidase MME gene is located at hum

    2022-05-20

    The membrane metalloendopeptidase (MME) gene is located at human chromosome 3q21-27. It encodes a 100-kD type II transmembrane glycoprotein, a widely expressed membrane metalloendopeptidase that degrades a number of substrates. The active site of the enzyme faces the extracellular space. MME is widely expressed in a broad range of tissues and particularly in kidney and lung tissues it got abundant expression. The molecule was first identified as a tumor-specific antigen (common acute lymphoblastic leukemia (ALL) antigen) in leukemia and has been used for diagnosing B-lineage ALL in combination with other B-lineage markers. Its expression can indicate prognosis in ALL. Although researchers have observed associations between MME expression and a few types of cancer, the specific association remains obscure. Interestingly, in some cancer, such as colorectal carcinoma, pancreatic endocrine tumor, and advanced melanomas, MME is overexpressed . In some types of tumor, most notably lung cancers and ovarian cancer, MME is down-regulated. In prostatic carcinoma (PC), MME is expressed in androgen-sensitive LNCaP 76 7 and possesses tumor suppressive ability . MME not only is a cell surface marker but also has a critical role in regulating many biological processes . However, the role of MME has not been investigated in the ESCC oncogenesis and progression. In this study, the clinical relevance of MME expression was investigated in human ESCC samples. MME down-regulation was correlated with poorer prognosis of ESCC patients. Also, MME introduction inhibited tumor cell metastasis, while not affecting tumor cell proliferation. The underlying mechanism of how MME inhibits ESCC tumor cell was also explored. Materials and methods
    Results
    Discussion Tumor metastasis is an important cause of human cancer-related deaths[21], [22]. The poor clinical outcome of ESCC is mainly attributed to its nature to metastasize and invade easily. It has been reported that skipped metastasis was observed in 60% of early esophageal cancer patients, making it urgent to uncover the molecular mechanisms of ESCC metastasis, and identify and characterize molecules that are responsible for ESCC metastasis. MME is a cell surface zinc metalloprotease. It is widely expressed in a variety of normal cell types. Firstly identified as an oncogene in leukemia (4), it has been studied in several different types of cancer. It seems that the function of MME in cancer is cell-type–dependent: In colorectal cancer patients, tumoral MME expression has been substantially associated with liver metastasis . MME positive expression correlates with tumor progression in pancreatic endocrine tumor and malignant melanoma. In ovarian cancer, however, low MME expression may indicate poor outcome (response to platinum) for patients. In prostate cancer, a better prognosis was predicted in the MME positive group[10], [30]. Conflicting results have been reported in bladder carcinoma: MME higher expression was reported in noninvasive carcinomas by one study, however, its up-regulation facilitated tumor invasion and dissemination in another study. In this study, down-regulation of MME was markedly associated with advanced clinical stage (P = 0.04), lymph node metastasis (P = 0.024), and poorer prognosis (P < 0.001). Multivariate analyses demonstrated that MME down-regulation was an independent prognostic factor for OS. In vitro and in vivo assays proved that MME could suppress ESCC cell motility but had no influence on ESCC cell proliferation. To find the mechanism responsible for metastasis inhibition, cell adhesion assay was performed in which MME overexpression was found to weaken cell adhesion ability. In most epithelia, FAK is a mediator for transducing signals at the focal adhesion complex facilitating cell migration [33], [34]. Consistent with previous report, MME overexpression led to a decreased phosphorylation of FAK (Tyr397); however the total FAK protein level remained unchanged, suggesting that MME overexpression inhibited FAK activation.