In proximal tubular epithelial cell

In proximal tubular epithelial cells, AEG‑1/MTDH is important in TGF‑β1‑induced epithelial‑mesenchymal transition (EMT) through activation of p38 MAPK (33). A recent study has suggested that AEG‑1/MTDH contributes to the pathogenesis of diffuse large B‑cell lymphoma mediated through regulation of the Wnt/β‑catenin pathway (34).
Furthermore, in the carcinogenesis of acute myeloid leukemia (AML), a novel functional link has been revealed between AEG‑1/MTDH and Aurora A kinase (AURKA) with regard to Akt1 activation (35). In human AML cells, AEG‑1/MTDH overexpression is vital for the maintenance of the malignant state via upregulation of Akt1, which is mediated by AURKA activation (35). In breast cancer cells, AEG‑1/MTDH facilitates cancer proliferation and invasion by upregulating HER2/neu expression (36).
Angiogenesis and metastasis. AEG‑1/MTDH overexpression converts non‑tumorigenic human HCC cells into highly aggressive vascular tumors. In addition, AEG‑1/MTDH modulates the expression of genes associated with invasion, angiogenesis, metastasis, chemoresistance and senescence, as determined by microarray analysis (15). AEG‑1/MTDH has a dominant function in regulating oncogenic transformation and angiogenesis (37). AEG‑1/MTDH expression is also increased in multiple cancers and is crucial in oncogenic transformation and angiogenesis (38‑41). In a phage display study, Brown and Ruoslahti (10) identified that a lung homing domain (amino acids 378‑440 in mice and 381‑443 in humans) in AEG‑1/MTDH was a mediator of 4T1 mouse mammary tumor cell adhesion to the lung vasculature, and suggested that AEG‑1/MTDH is important in breast cancer metastasis. In CRC, Jiang et al (18) showed that AEG‑1/MTDH is overexpressed in liver metastasis patients compared with patients without liver metastasis. In addition, AEG‑1/MTDH may present as a potential novel biomarker for early liver metastasis. In a large proportion of epithelial ovarian cancer patients with peritoneal dissemination and/or lymph node metastasis, AEG‑1/MTDH is overexpressed and is a novel predictor of metastasis (42). In summary, AEG‑1/MTDH is crucial in lymph node metastasis (39,43‑45) and contributes to tumor progression, including transformation, the evasion of apoptosis, invasion and metastasis (13).
Chemoresistance. One of the important hallmarks of aggressive cancers is chemoresistance. Previous studies have suggested that AEG‑1/MTDH contributes to a broad spectrum of resistance to various chemotherapeutics, including 5‑fluorouracil, doxorubicin, paclitaxel, cisplatin and 4‑hydroxycyclophosphamide (16,46‑48). In human HCC cells, the gene expression profiles of overexpressed AEG‑1/MTDH have been identified in several drug‑metabolizing enzymes involved in chemoresistance, including dihydropyrimidine dehydrogenase, cytochrome P450B6, dihydrodiol dehydrogenase, ATP‑binding cassette transporter 11/MRP8 and transcription factor LSF/TFCP2 (15). AEG‑1/MTDH increases multidrug‑resistance gene 1 (MDR1) protein expression, which facilitates the association between MDR1 mRNA and polysomes, leading to increased translation, the inhibition of ubiquitination and the resultant proteasome‑mediated degradation of the MDR1 protein (47). The inhibition of AEG‑1/MTDH may be an effective method in HCC chemotherapy (47). Bhutia et al (49) also showed that protective autophagy is the cause of AEG‑1‑mediated chemoresistance, and that the inhibition of AEG‑1/MTDH results in a decrease in the protective autophagy and chemosensitization of cancer cells. Due to the multiple functions of AEG‑1/MTDH in drug resistance, AEG‑1/MTDH is a viable target as an anticancer agent for a wide range of cancer types (50).
Recent results have also indicated that AEG‑1/MTDH affects the radiosensitivity of cervical cancer cells (51). In summary, it has become apparent that AEG‑1/MTDH is an important oncogene, which is overexpressed in numerous human cancer types. Through a number of signaling cascades, AEG‑1/MTDH is involved in several crucial aspects of tumor progression, including transformation, proliferation, the evasion of apoptosis, cell survival, migration and invasion, angiogenesis, metastasis and chemoresistance (52). Future studies are required to evaluate the correlation between AEG‑1/MTDH function and signaling changes and interacting partners in order to highlight novel perspectives for AEG‑1/MTDH as a significant target for the clinical treatment of various cancers.

結果 (中文) 3:

近端肾小管上皮细胞，AEG‑1 / MTDH在TGF-β1诱导上皮间质‑β‑‑过渡的重要（EMT）通过激活p38 MAPK信号通路（33）。最近的一项研究表明，AEG‑1 / MTDH导致弥漫性大B细胞淋巴瘤的发病机制‑介导Wnt/β-catenin通路的β‑调节（34）。此外，在急性髓系白血病（AML）中，一个新的功能链接已被发现之间的AEG‑1 / MTDH和极光激酶A（AURKA）针对Akt1激活（35）。在人类白血病细胞，AEG‑1 / MTDH表达是非常重要的恶性状态检修通过上调AKT1，由AURKA活化介导的（35）。在乳腺癌细胞中，AEG‑1 / MTDH促进癌细胞增殖和侵袭的HER2/neu表达上调（36）。血管生成与转移。AEG‑1 / MTDH表达将非‑致瘤性人肝癌细胞为高度侵袭性血管瘤。此外，AEG‑1 / MTDH调节侵袭、血管生成、肿瘤转移相关基因的表达，细胞衰老，通过微阵列分析确定（15）。AEG‑1 / MTDH在调节细胞恶性转化和肿瘤血管生成的具有主导作用（37）。AEG‑1 / MTDH表达在多种癌症的增加，在细胞恶性转化和肿瘤血管生成的关键（38‑41）。在噬菌体的研究中，布朗和鲁奥斯拉蒂（10）发现肺归巢域（378个氨基酸‑440小鼠和381‑443人）在AEG‑1 / MTDH调停人4T1小鼠乳腺癌细胞粘附于肺血管，并建议AEG‑MTDH在1 /乳腺癌转移的重要。在CRC，江等人（18）表明，AEG‑1 / MTDH的过度表达在肝转移患者较无肝转移患者。此外，AEG‑1 / MTDH可能表现为早期肝转移的一个潜在的生物标志物。在一个大比例的卵巢上皮癌患者腹膜和/或淋巴结转移，AEG‑1 / MTDH表达是一种新型的预测转移（42）。总之，AEG‑1 / MTDH在淋巴结转移的关键（39,43‑45），有助于肿瘤的进展，包括转化、细胞凋亡的回避、侵袭和转移（13）。耐药。一个重要的特征是恶性肿瘤化疗耐药。以往的研究表明，AEG‑1 / MTDH有广谱的抗多种药物，包括5‑氟尿嘧啶、阿霉素、紫杉醇、顺铂和4‑羟基皮质酮（16,46‑48）。在人肝癌细胞中高表达，AEG‑1 / MTDH基因表达谱的变化已经在一些药物‑代谢酶参与耐药的确定，包括二氢嘧啶脱氢酶、细胞色素p450b6、脱氢酶、ATP结合盒转运体11‑MRP8和转录因子LSF / tfcp2（15）。AEG‑1 / MTDH增加多药‑耐药基因1（MDR1）蛋白的表达，这有利于mdr1 mRNA和核糖体之间的关联，从而增加了翻译、介导MDR1蛋白降解的泛素蛋白酶体抑制和所得‑（47）。AEG‑1 / MTDH的抑制可能是肝癌治疗的一种有效方法（47）。菩提亚等人（49）也表明，保护性自噬是AEG‑1‑原因介导耐药，而AEG‑1 / MTDH结果在和癌细胞的化疗增敏作用的保护性自噬减少抑制。由于AEG‑1 / MTDH在耐药的多重功能，AEG‑1 / MTDH是一个可行的目标为一个范围广泛的癌症类型的抗癌剂（50）。最近的研究结果也表明，AEG‑1 / MTDH影响宫颈癌细胞的放射敏感性（51）。总之，它已成为明显的，AEG‑1 / MTDH基因是一种重要的癌基因，这是在许多人类癌症中过度表达。通过一系列的信号级联，AEG‑1 / MTDH基因参与肿瘤的进展，一些关键的方面包括转化、增殖、凋亡、逃避细胞存活、迁移、侵袭、血管生成、转移和耐药（52）。未来的研究需要评估AEG‑1 / MTDH功能和信号的变化和相互作用的合作伙伴，为了突出新的观点‑AEG 1 MTDH作为重要目标为临床治疗各种癌症的关系。