The vacuolar-ATPase modulates matrix metalloproteinase isoforms in human pancreatic cancer.
The vacuolar-ATPase modulates matrix metalloproteinase isoforms in human pancreatic cancer.
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DOI：
10.1038/labinvest.2011.8
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发表时间：
2011-05
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--
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液泡-ATP酶（vacuolar-ATPase，v-ATPase）是一种质子转运蛋白，存在于细胞内的许多细胞器和质膜上。癌细胞PM上的v-ATPase可能与其体外侵袭性有关。其与人类癌症组织的相关性仍不清楚。我们研究了v-ATPase的表达和细胞定位是否与人胰腺癌的分期相对应，以及其对基质金属蛋白酶（MMP）激活的影响。从正常导管到胰腺上皮内肿瘤（PanIN），最后是胰腺导管腺癌（PDAC），胰腺组织学范围内v-ATP酶染色强度显著增加。在大多数（86%）检查的视野中，低级别PanIN病变显示局限于细胞基底面的极化染色。高级别PanIN病变和PDAC表现出强烈和弥漫性v-ATP酶定位。在胰腺癌细胞中，PM相关的v-ATP酶与coronin共定位，coronin是帮助直接MMP释放的前沿成分。用Concanamycin或靶向V1 E亚基的shRNA阻断v-ATP酶可降低MMP-9活性;这种效应在具有显著PM相关v-ATP酶的细胞中最大。然而，在可检测到MMP-2活性的细胞中，用康卡那霉素治疗显著增加了MMP-2的最活化形式。V-ATP酶阻断抑制功能的迁移和侵袭，这些细胞主要与MMP-9的活性。这些结果表明，人PDAC标本显示v-ATP酶极性丧失和表达增加，这与侵袭性增加相关。因此，v-ATP酶选择性地调节可能与侵袭性癌症表型相关的特异性MMP。
The vacuolar-ATPase (v-ATPase) is a proton transporter found on many intra-cellular organelles and the plasma membrane (PM). The v-ATPase on PMs of cancer cells may contribute to their invasive properties in vitro. Its relevance to human cancer tissues remains unclear. We investigated whether the expression and cellular localization of v-ATPase corresponded to the stage of human pancreatic cancer, and its effect on matrix metalloproteinase (MMP) activation in vitro. The intensity of v-ATPase staining increased significantly across the range of pancreatic histology from normal ducts to pancreatic intra-epithelial neoplasms (PanIN) and finally pancreatic ductal adenocarcinoma (PDAC). Low-grade PanIN lesions displayed polarized staining confined to the basal aspect of the cell in the majority (86%) of fields examined. High-grade PanIN lesions and PDAC demonstrated intense and diffuse v-ATPase localization. In pancreatic cancer cells, PM-associated v-ATPase co-localized with cortactin, a component of the leading edge that helps direct MMP release. Blockade of the v-ATPase with concanamycin or shRNA targeting the V1E subunit reduced MMP-9 activity; this effect was greatest in cells with prominent PM-associated v-ATPase. In cells with detectable MMP-2 activities, however, treatment with concanamycin markedly increased MMP-2’s most activated forms. V-ATPase blockade inhibited functional migration and invasion in those cells with predominantly MMP-9 activity. These results indicate that human PDAC specimens demonstrate loss of v-ATPase polarity and increased expression that correlates with increasing invasive potential. Thus, v-ATPase selectively modulates specific MMPs that may be linked to an invasive cancer phenotype.
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