Tricellular tight junction protein LSR/angulin-1 contributes to the epithelial barrier and malignancy in human pancreatic cancer cell line
Tricellular tight junction protein LSR/angulin-1 contributes to the epithelial barrier and malignancy in human pancreatic cancer cell line
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DOI：
10.1007/s00418-019-01821-4
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发表时间：
2019-10-24
影响因子：
2.3
通讯作者：
Kojima, Takashi
中科院分区：
文献类型：
--
作者：
Kyuno, Takuro;Kyuno, Daisuke;Kojima, Takashi
脂解刺激的脂蛋白受体（LSR）/angulin-1是正常细胞上皮屏障和癌细胞恶性肿瘤中三细胞接触的关键分子。为了研究LSR/angulin-1是否影响人胰腺癌的上皮屏障和恶性程度，使用了人胰腺癌细胞系HPAC。用EGF或TGF-β处理增加LSR的表达，但不增加三细胞素（TRIC）的表达，并诱导LSR和TRIC从三细胞紧密连接定位到双细胞紧密连接。TGF-β 1型受体抑制剂EW-7197阻止了TGF-β引起的LSR分布和屏障功能的改变。LSR的敲低增加了细胞的迁移、侵袭、增殖和EGF配体双调蛋白的表达，并降低了上皮屏障。用双调蛋白诱导细胞迁移和侵袭，敲低双调蛋白可阻止由敲低LSR引起的细胞迁移、侵袭和增殖的增加。用LSR配体肽angubindin-1处理降低了上皮屏障和LSR的表达，但没有TRIC，并增加了细胞侵袭。TRIC的敲除降低了细胞迁移和上皮屏障。在人胰腺癌组织的免疫组化分析中，发现LSR和TRIC定位于正常胰腺导管和高分化胰腺导管腺癌（PDAC）的细胞膜上，而在低分化PDAC中，LSR在细胞质中被微弱地检测到。双调蛋白在分化良好和分化不良的PDAC细胞质中高度表达。在胰腺癌中，LSR通过生长因子促进上皮屏障的形成和恶性化，可能成为治疗胰腺癌的潜在靶分子。
Lipolysis-stimulated lipoprotein receptor (LSR)/angulin-1 is a crucial molecule of tricellular contacts in the epithelial barrier of normal cells and the malignancy of cancer cells. To investigate whether LSR/angulin-1 affects the epithelial barrier and malignancy in human pancreatic cancer, human pancreatic cancer cell line HPAC was used. Treatment with EGF or TGF-beta increased the expression of LSR, but not tricellulin (TRIC), and induced the localization of LSR and TRIC to bicellular tight junctions from tricellular tight junctions. TGF-beta receptor type-1 inhibitor EW-7197 prevented changes of the distribution and the barrier function of LSR by TGF-beta. Knockdown of LSR increased cell migration, invasion, proliferation and EGF ligand amphiregulin expression and decreased the epithelial barrier. Treatment with amphiregulin induced cell migration and invasion and knockdown of amphiregulin prevented the increases of cell migration, invasion and proliferation caused by knockdown of LSR. Treatment with LSR ligand peptide angubindin-1 decreased the epithelial barrier and the expression of LSR, but not TRIC, and increased cell invasion. Knockdown of TRIC decreased cell migration and the epithelial barrier. In immunohistochemical analysis of human pancreatic cancer tissues, LSR and TRIC were found to be localized at the cell membranes of normal pancreatic ducts and well-differentiated pancreatic ductal adenocarcinomas (PDAC), whereas in poorly differentiated PDAC, LSR was weakly detected in the cytoplasm. Amphiregulin was highly expressed in the cytoplasm of well- and poorly differentiated PDAC. In pancreatic cancer, LSR contributes to the epithelial barrier and malignancy via growth factors and may be a potential targeting molecule in the therapy.