Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People's Republic of China.
Department of Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Aug;397(8):6093-6106. doi: 10.1007/s00210-024-03003-z. Epub 2024 Feb 28.
Integrin β6 (ITGB6) is upregulated in multiple tumor types and elevated ITGB6 levels have been detected in patients with chronic pancreatitis. However, the role of ITGB6 in pancreatic fibrosis and cancer remains to be elucidated. In the present study, ITGB6 expression was assessed using western blotting and qRT-PCR. Besides, cell proliferation, cycling, migration, and invasion were evaluated using CCK-8, flow cytometry, wound healing, and transwell assays, respectively. The expression of fibrosis and JAK2/STAT3 signaling markers was detected by western blotting and immunofluorescence analysis. Moreover, nude mice were subcutaneously injected with co-cultured cell suspensions to establish an in vivo model. The results showed that ITGB6 was highly expressed in pancreatic cancer tissues and TGF-β-induced pancreatic stellate cells (PSCs). Inhibition of ITGB6 expression in PSCs resulted in clear inhibition of activated PSC proliferation, migration, and fibrogenesis. Additionally, reduced ITGB6 expression inhibits the JAK2/STAT3 signaling pathway. Interestingly, activators of the JAK2/STAT3 signaling pathway reversed the effects of ITGB6 disruption on PSCs. Activated PSCs notably promoted the proliferation, invasion, and migration of pancreatic cancer cells in a co-culture assay. In contrast, activated PSCs with low ITGB6 expression failed to significantly affect the malignancy of pancreatic cancer cells. Moreover, in vivo results showed that interference with ITGB6 inhibited the activation of PSCs and promoted the development of pancreatic cancer. Silencing ITGB6 inhibited the proliferation, migration, and fibrosis-like effects of activated PSCs and indirectly inhibited the metastasis and malignant process of pancreatic cancer by inhibiting the JAK2/STAT3 signaling pathway. Therefore, ITGB6 is a potential candidate target for pancreatic cancer prevention and treatment.
整合素 β6（ITGB6）在多种肿瘤类型中上调，慢性胰腺炎患者中检测到升高的 ITGB6 水平。然而，ITGB6 在胰腺纤维化和癌症中的作用仍有待阐明。在本研究中，使用 Western blot 和 qRT-PCR 评估了 ITGB6 的表达。此外，分别使用 CCK-8、流式细胞术、划痕愈合和 Transwell 测定评估了细胞增殖、细胞周期、迁移和侵袭。通过 Western blot 和免疫荧光分析检测纤维化和 JAK2/STAT3 信号标记物的表达。此外，通过皮下注射共培养细胞混悬液建立了体内模型。结果表明，ITGB6 在胰腺癌组织和 TGF-β诱导的胰腺星状细胞（PSC）中高表达。PSC 中 ITGB6 表达的抑制导致活化 PSC 的增殖、迁移和纤维发生明显抑制。此外，降低 ITGB6 表达抑制 JAK2/STAT3 信号通路。有趣的是，JAK2/STAT3 信号通路的激活剂逆转了 ITGB6 破坏对 PSC 的影响。活化的 PSCs 在共培养测定中显著促进了胰腺癌细胞的增殖、侵袭和迁移。相比之下，低 ITGB6 表达的活化 PSCs 未能显著影响胰腺癌细胞的恶性程度。此外，体内结果表明，干扰 ITGB6 抑制 PSC 的激活并促进胰腺癌的发展。沉默 ITGB6 抑制活化 PSCs 的增殖、迁移和纤维化样作用，并通过抑制 JAK2/STAT3 信号通路间接抑制胰腺癌的转移和恶性进程。因此，ITGB6 是预防和治疗胰腺癌的潜在候选靶标。
