Department of Pathology & Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Int J Cancer. 2023 Aug 1;153(3):552-570. doi: 10.1002/ijc.34528. Epub 2023 May 4.
Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a noncanonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the protumoral role of KMT2D loss. These findings support a tumor-suppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.
尽管 KMT2D（也称为 MLL2）已知在发育、分化和肿瘤抑制中发挥重要作用，但它在胰腺癌发展中的作用尚不清楚。在这里，我们发现了一条由 KMT2D 介导的新信号通路，它将 TGF-β 与激活素 A 途径联系起来。我们发现 TGF-β 上调了 microRNA miR-147b，后者反过来导致 KMT2D 的转录后沉默。KMT2D 的缺失诱导激活素 A 的表达和分泌，激活非典型的 p38 MAPK 介导的途径，调节癌细胞可塑性，促进间充质表型，并增强小鼠的肿瘤侵袭和转移。我们观察到人类原发性和转移性胰腺癌中 KMT2D 的表达降低。此外，抑制或敲低激活素 A 可逆转 KMT2D 缺失的促肿瘤作用。这些发现支持 KMT2D 在胰腺癌中的肿瘤抑制作用，并确定 miR-147b 和激活素 A 为新的治疗靶点。
