Integrin beta 4 (ITGB4) and its tyrosine-1510 phosphorylation promote pancreatic tumorigenesis and regulate the MEK1-ERK1/2 signaling pathway
Integrin beta 4 (ITGB4) and its tyrosine-1510 phosphorylation promote pancreatic tumorigenesis and regulate the MEK1-ERK1/2 signaling pathway
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DOI：
10.17305/bjbms.2019.4255
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发表时间：
2020-01-01
影响因子：
3.4
通讯作者：
Tan, Xiaodong
中科院分区：
文献类型：
--
作者：
Meng, Xiangli;Liu, Peng;Tan, Xiaodong
胰腺癌是癌症死亡的第四大原因，5年生存率仅为1- 4%。整合素介导的细胞粘附对于癌症的发生、进展和转移至关重要。在这项研究中，我们研究了整合素β 4（ITGB 4）及其酪氨酸Y1510磷酸化（p-ITGB 4-Y1510）在胰腺癌肿瘤发生中的作用。我们使用免疫组织化学、Western印迹或半定量逆转录PCR分析了ITGB 4和p-ITGB 4-Y1510在胰腺癌组织和细胞系中的表达。ITGB 4和p-ITGB 4。Y1510在胰腺癌组织（n = 176）中的表达高于正常胰腺组织（n = 171）。p-ITGB 4-Y1510高表达与胰腺癌的局部浸润和远处转移相关，ITGB 4高表达与患者的生存率显著相关。通过siRNA抑制ITGB 4显著降低PC-1.0和AsPC-1细胞的迁移和侵袭。在PC-1.0和AsPC-1细胞中过表达突变体ITGB 4-Y1510（在isio位置处酪氨酸突变为丙氨酸）不仅阻断ITGB 4在Yisio处的磷酸化，而且抑制ITGB 4的表达（与野生型ITGB 4相比p < 0.05）。用ITGB 4-Y1510 A转染PC-1.0和AsPC-1细胞显著降低了p-mitogen-activated protein kinase kinase（MEK）1（T292）和p-extracellular signal-regulated kinase（ERK）1/2的水平，但不影响p-MEK 1（T386）和p-MEK 2（T394）的水平。总之，我们的研究表明，ITGB 4及其磷酸化形式促进胰腺癌细胞的迁移和侵袭，p-ITGB 4-Y1510调节下游MEK 1-ERK 1/2信号级联。靶向ITGB 4或其在Yisio的磷酸化可能是胰腺癌的一种新的治疗选择。
Pancreatic cancer is the fourth leading cause of cancer death, with a 5-year survival rate of only 1-4%. Integrin-mediated cell adhesion is critical for the initiation, progression, and metastasis of cancer. In this study we investigated the role of integrin beta 4 (ITGB4) and its phosphorylation at tyrosine Y1510 (p-ITGB4-Y1510) in the tumorigenesis of pancreatic cancer. We analyzed the expression of ITGB4 and p-ITGB4-Y1510 in pancreatic cancer tissue and cell lines using immunohistochemistry, Western blot, or semi-quantitative reverse transcription PCR. ITGB4 and p-ITGB4.-Y1510 were highly expressed in pancreatic cancer (n = 176) compared with normal pancreatic tissue (n = 171). High p-ITGB4-Y1510 expression correlated with local invasion and distant metastasis of pancreatic cancer, and high ITGB4 was significantly associated with poor survival of patients. Inhibition of ITGB4 by siRNA significantly reduced migration and invasion of PC-1.0 and AsPC-1 cells. Overexpression of the mutant ITGB4-Y1510 (a mutation of tyrosine to alanine at isio position) in PC-1.0 and AsPC-1 cells not only blocked the ITGB4 phosphorylation at Yisio but also suppressed the expression of ITGB4 (p < 0.05 vs. wild-type ITGB4). The transfection of PC-1.0 and AsPC-1 cells with ITGB4-Y1510 A significantly decreased the level of p-mitogen-activated protein kinase kinase (MEK)1 (T292) and p-extracellular signal-regulated kinase (ERK)1/2 but did not affect the level of p-MEK1 (T 386) and p-MEK2 (T394). Overall, our study showed that ITGB4 and its phosphorylated form promote cell migration and invasion in pancreatic cancer and that p-ITGB4-Y1510 regulates the downstream MEK1-ERK1/2 signaling cascades. Targeting ITGB4 or its phosphorylation at Yisio may be a novel therapeutic option for pancreatic cancer.