KMT2D links TGF-β signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity.
KMT2D links TGF-β signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity.
复制标题
KMT2D 将 TGF-β 信号传导与非经典激活素途径联系起来，并调节胰腺癌细胞的可塑性。
DOI：
10.1002/ijc.34528
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发表时间：
2023
影响因子：
6.4
通讯作者：
Ljun
中科院分区：
文献类型：
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作者：
Lu,Shuang;Kim,HongSun;Cao,Yubo;Bedi,Karan;Zhao,Lili;Narayanan,IshwaryaVenkata;Magnuson,Brian;Gu,Yumei;Yang,Jing;Yi,Zhujun;Babaniamansour,Sepideh;Shameon,Sargis;Xu,Chang;Paulsen,MichelleT;Qiu,Ping;Jeyarajan,Sivakumar;Ljun
虽然KMT2D，也被称为MLL2，已知在胰腺癌的发生、分化和肿瘤抑制中发挥重要作用，但它在胰腺癌发生中的作用尚不清楚。在这里，我们发现了一个由KMT2D介导的新的信号轴，它将转化生长因子-β与激活素A途径联系起来。我们发现转化生长因子-β上调了一个microRNA，miR-147b，这反过来又导致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p38MAPK介导的非规范途径，调节肿瘤细胞的可塑性，促进间充质表型，增强肿瘤的侵袭和转移。我们观察到KMT2D在人类原发和转移性胰腺癌中的表达降低。此外，抑制或敲除激活素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，并将miR-147b和激活素A确定为新的治疗靶点。
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.