Department of the First General Surgery, Shengjing Hospital affiliated to China Medical University, Shenyang, China.
Department of Anus and Intestine Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Bosn J Basic Med Sci. 2020 Feb 5;20(1):106-116. doi: 10.17305/bjbms.2019.4255.
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 b4 (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-Y1510A (a mutation of tyrosine to alanine at 1510 position) in PC-1.0 and AsPC-1 cells not only blocked the ITGB4 phosphorylation at Y1510 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-Y1510A 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 (T386) 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 Y1510 may be a novel therapeutic option for pancreatic cancer.
胰腺癌是癌症死亡的第四大主要原因，其 5 年生存率仅为 1%-4%。整合素介导的细胞黏附对于癌症的起始、进展和转移至关重要。在这项研究中，我们研究了整合素 b4（ITGB4）及其酪氨酸 Y1510 磷酸化（p-ITGB4-Y1510）在胰腺癌发生中的作用。我们使用免疫组织化学、Western blot 或半定量逆转录 PCR 分析了胰腺癌组织和细胞系中 ITGB4 和 p-ITGB4-Y1510 的表达。与正常胰腺组织（n=171）相比，ITGB4 和 p-ITGB4-Y1510 在胰腺癌（n=176）中高表达。p-ITGB4-Y1510 的高表达与胰腺癌的局部浸润和远处转移相关，而 ITGB4 的高表达与患者的生存不良显著相关。用 siRNA 抑制 ITGB4 显著降低了 PC-1.0 和 AsPC-1 细胞的迁移和侵袭。在 PC-1.0 和 AsPC-1 细胞中转染突变型 ITGB4-Y1510A（酪氨酸 1510 位突变为丙氨酸）不仅阻断了 Y1510 处的 ITGB4 磷酸化，而且还抑制了 ITGB4 的表达（与野生型 ITGB4 相比，p<0.05）。用 ITGB4-Y1510A 转染 PC-1.0 和 AsPC-1 细胞显著降低了 p-丝裂原激活的蛋白激酶激酶 1（MEK1）（T292）和 p-细胞外信号调节激酶 1/2（ERK1/2）的水平，但不影响 p-MEK1（T386）和 p-MEK2（T394）的水平。总的来说，我们的研究表明，ITGB4 及其磷酸化形式促进了胰腺癌中的细胞迁移和侵袭，而 p-ITGB4-Y1510 调节下游的 MEK1-ERK1/2 信号级联。靶向 ITGB4 或其 Y1510 磷酸化可能是胰腺癌的一种新的治疗选择。
