降低、浸润深度的加深、淋巴转移的发生、远隔转移的产生及临床分期的增高而降低(P<0.05), 与文献报道相符, 提示PTEN基因表达的缺失与胃癌的发生、发展、浸润和转移密切相关, 而且可能为判断胃癌的恶性程度提供依据。
细胞外基质(extracellular matrix, ECM)和基底膜(basement membrane)降解是恶性肿瘤浸润和转移的关键环节。基质金属蛋白酶(matrixmetallo-proteinases, MMPs)的作用底物是细胞外基质和基底膜中的纤维网架分子。基质金属蛋白酶-9(metrix metalloproteinase-9, MMP-9)属于其中的明胶酶类, 通常以酶原的形式合成, 被激活后可特异性地降解细胞外基质和基底膜中的主要成分Ⅳ型胶原。MMP-9不仅主要在癌细胞中表达, 而且基质中的纤维母细胞、单核吞噬细胞中也有表达, 其阳性表达以浸润癌巢周围最明显, 说明它与肿瘤的浸润密切相关
[10]
。 MMP-9还能和VEGF协同作用参与肿瘤血管的生成[11]。MMP-9还能释放
血管内皮生长因子(VEGF)来促进肿瘤新生血管的形成, 同时, VEGF的高表达也刺激了MMP-9的过度分泌。二者相互作用, 共同促进肿瘤的发生、发展. MMP-9的多重作用促使肿瘤细胞的形成、浸润及转移, 所以MMP-9是评价肿瘤患者状况和预后不良的重要因素。有研究表明乳腺癌细胞、肝癌、结肠癌和小细胞肺癌及其间质均可表达MMPs, 在机体免疫监视低下的情况下, MMP-9通过破坏基底膜中的Ⅳ型胶原, 进行肿瘤的浸润与转移。研究发现MMP-9在胃癌中的表达与肿瘤生长方式、浸润深度、淋巴转移、病理分化、远隔转移及患者的不良预后相关[12-13]. 我们发现, MMP-9在胃癌组织中的表达率明显高于在正常胃组织中的表达, 并随肿瘤病理分化程度的降低、浸润深度的加深、淋巴转移的发生、临床分期的增高而增加(P<0.05), 与文献报道相符, 提示MMP-9的高表达与胃癌的发生、发展、侵袭与转移密切相关。
研究发现PTEN能负性调控MMP-9而抑制细胞外基质和基底膜降解, 抑制肿瘤浸润和转移[14-19]。 我们发现, PTEN和MMP-9在胃癌组织中的表达呈负相关(r=-0.257，P=0.019), MMP-9的表达随PTEN的降低而升高, 提示胃癌组织中PTEN表达的缺失, 导致了对MMP-9的抑制作用降低, 而使MMP-9高表达, 促进了肿瘤细胞的侵袭和转移。PTEN的突变或缺失可能为初始因素, 激活Akt, 而活化的Akt可通过磷酸化IKK、IKB, IKB降解释放NF-κB转位入细胞核, 在MMP-9调控区调节MMP-9的表达, Fukuyama et al[18]研究表明在结肠癌中,
TNF-α诱导MMP-9表达主要受NF-KB的调控。还有研究发现PTEN可能增加MMP-9的抑制物TIMP-1的分泌[19], 证实了 PTEN可从多条途径抑制MMP-9的表达, 抑制肿瘤的侵袭与转移, 当PTEN表达缺失时, PTEN对MMP-9的抑制作用减弱, 促进了肿瘤的转移.
本实验通过免疫组化方法联合检测PTEN和MMP-9, 进一步明确二者在胃癌发展中的异常表达及相关性, 从而明确MMP-9和PTEN在胃癌中的发病机制, 所以检测PTEN和MMP-9不但能提高胃癌早期的诊断率, 还能了解胃癌的发生发展机制，为评估胃癌的进展情况和预后提供依据, 可作为评估胃癌的生物学行为及预后的重要参考指标, 同时也为临床中应用MMP-9的抑制剂和PTEN的激活剂提供新的基础, 为胃癌诊断、治疗、预后提供新的途径。
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PTEN和MMP-9在胃癌组织中的表达及其临床意义 - 图文
