MUC13 mucin augments pancreatic tumorigenesis.
MUC13 mucin augments pancreatic tumorigenesis.
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DOI：
10.1158/1535-7163.mct-11-0598
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发表时间：
2012-01
影响因子：
5.7
通讯作者：
Jaggi M
中科院分区：
文献类型：
--
作者：
Chauhan SC;Ebeling MC;Maher DM;Koch MD;Watanabe A;Aburatani H;Lio Y;Jaggi M
胰腺癌的高死亡率归因于缺乏可靠的早期检测方法和其侵袭性发病机制的潜在分子机制。尽管MUC 13是一种新发现的跨膜粘蛋白，已知其在卵巢癌和胃肠道癌中异常表达，但其在胰腺癌中的作用尚不清楚。在此，我们研究了MUC 13在胰腺癌进展中的表达谱和功能。使用最近产生的单克隆抗体（克隆PPZ 0020）和胰腺组织微阵列研究胰腺癌中MUC 13的表达谱。MUC 13在胰腺癌组织中的表达显著高于正常胰腺组织和非肿瘤胰腺组织（P < 0.005）。对于功能分析，全长MUC 13在MUC 13无效胰腺癌细胞系MiaPaca和Pancl中表达。MUC 13过表达可显著增加细胞的运动性、侵袭性、增殖性、贴壁依赖性或非贴壁依赖性克隆形成能力（P < 0.05），同时降低细胞间和细胞-基质间的粘附性。在异种移植小鼠模型中，外源性MUC 13表达显著（P < 0.05）增强胰腺肿瘤生长并降低动物存活率。这些致瘤特征与HER 2、p21激活激酶1（PAK 1）、细胞外信号调节激酶（ERK）、Akt和S100 A4的上调/磷酸化以及p53的抑制相关。相反，通过短发夹RNA抑制HPAFII胰腺癌细胞中的MUC 13导致肿瘤发生特征的抑制、HER 2、PAK 1、ERK和S100 A4的抑制以及p53的上调。MUC 13抑制也显著（P < 0.05）减少肿瘤生长并增加动物存活。这些结果暗示了MUC 13在胰腺癌中的作用，并表明其作为诊断和治疗靶点的潜在用途。
The high death rate of pancreatic cancer is attributed to the lack of reliable methods for early detection and underlying molecular mechanisms of its aggressive pathogenesis. Although MUC13, a newly identified transmembrane mucin, is known to be aberrantly expressed in ovarian and gastro-intestinal cancers, its role in pancreatic cancer is unknown. Herein, we investigated the expression profile and functions of MUC13 in pancreatic cancer progression. The expression profile of MUC13 in pancreatic cancer was investigated using a recently generated monoclonal antibody (clone PPZ0020) and pancreatic tissue microarrays. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with normal/nonneoplastic pancreatic tissues. For functional analyses, full-length MUC13 was expressed in MUC13 null pancreatic cancer cell lines, MiaPaca and Panc1. MUC13 overexpression caused a significant (P < 0.05) increase in cell motility, invasion, proliferation, and anchorage-dependent or -independent clonogenicity while decreasing cell–cell and cell-substratum adhesion. Exogenous MUC13 expression significantly (P < 0.05) enhanced pancreatic tumor growth and reduced animal survival in a xenograft mouse model. These tumorigenic characteristics correlated with the upregulation/phosphorylation of HER2, p21-activated kinase 1 (PAK1), extracellular signal-regulated kinase (ERK), Akt, and metastasin (S100A4), and the suppression of p53. Conversely, suppression of MUC13 in HPAFII pancreatic cancer cells by short hairpin RNA resulted in suppression of tumorigenic characteristics, repression of HER2, PAK1, ERK, and S100A4, and upregulation of p53. MUC13 suppression also significantly (P < 0.05) reduced tumor growth and increased animal survival. These results imply a role of MUC13 in pancreatic cancer and suggest its potential use as a diagnostic and therapeutic target.