Sasaki Norihiko, Hirano Kazumi, Shichi Yuuki, Gomi Fujiya, Yoshimura Hisashi, Matsushita Akira, Toyoda Masashi, Ishiwata Toshiyuki
Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Molecular Neurophysiology Research Group, Biomedical Research Institute, The National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki 305-8568, Japan.
Cancers (Basel). 2022 Apr 19;14(9):2055. doi: 10.3390/cancers14092055.
Signaling pathways involving signal transducer and activator of transcription 3 (STAT3) play key roles in the aggressiveness of pancreatic ductal adenocarcinoma (PDAC), including their tumorigenesis, invasion, and metastasis. Cancer stem cells (CSCs) have been correlated with PDAC aggressiveness, and activation of STAT3 is involved in the regulation of CSC properties. Here, we investigated the involvement of interleukin-6 (IL-6) or the leukemia inhibitory factor (LIF)/glycoprotein 130 (gp130)/STAT3 pathway and their role in pancreatic CSCs. In PDAC CSC-like cells formed by culturing on a low attachment plate, autocrine/paracrine IL-6 or LIF contributes to gp130/STAT3 pathway activation. Using a gp130 inhibitor, we determined that the gp130/STAT3 pathway contributes to the maintenance of stemness features, the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), and the invasion of PDAC CSC-like cells. The gp130/STAT3 pathway also modulates the transforming growth factor (TGF)-β1/Smad pathway required for epithelial-mesenchymal transition induction through regulation of TGFβ-RII expression in PDAC CSC-like cells. Furthermore, chromatin immunoprecipitation assays revealed that p-STAT3 can access the active promoter region of to influence this metastasis-related long non-coding RNA and contribute to its transcription in PDAC CSC-like cells. Therefore, the autocrine/paracrine IL-6 or LIF/gp130/STAT3 pathway in PDAC CSC-like cells may eventually facilitate invasion and metastasis, two hallmarks of malignancy. We propose that inhibition of the gp130/STAT3 pathway provides a promising strategy for targeting CSCs for the treatment of PDAC.
涉及信号转导和转录激活因子3（STAT3）的信号通路在胰腺导管腺癌（PDAC）的侵袭性中起关键作用，包括其肿瘤发生、侵袭和转移。癌症干细胞（CSCs）与PDAC的侵袭性相关，STAT3的激活参与了CSC特性的调节。在此，我们研究了白细胞介素-6（IL-6）或白血病抑制因子（LIF）/糖蛋白130（gp130）/STAT3信号通路及其在胰腺CSCs中的作用。在低附着板上培养形成的PDAC CSC样细胞中，自分泌/旁分泌的IL-6或LIF有助于gp130/STAT3信号通路的激活。使用gp130抑制剂，我们确定gp130/STAT3信号通路有助于维持干性特征、膜型1基质金属蛋白酶（MT1-MMP）的表达以及PDAC CSC样细胞的侵袭。gp130/STAT3信号通路还通过调节PDAC CSC样细胞中TGFβ-RII的表达来调节上皮-间质转化诱导所需的转化生长因子（TGF）-β1/Smad信号通路。此外，染色质免疫沉淀分析表明，p-STAT3可以进入 的活性启动子区域，影响这种与转移相关的长链非编码RNA，并促进其在PDAC CSC样细胞中的转录。因此，PDAC CSC样细胞中的自分泌/旁分泌IL-6或LIF/gp130/STAT3信号通路最终可能促进侵袭和转移，这是恶性肿瘤的两个标志。我们提出，抑制gp130/STAT3信号通路为靶向CSCs治疗PDAC提供了一种有前景的策略。
