KMT2D links TGF- β signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity

被引：11

作者：

Lu, Shuang ^{[1
,2
,3
]}

Kim, Hong Sun ^{[1
,2
]}

Cao, Yubo ^{[1
,2
]}

Bedi, Karan ^{[2
,4
]}

Zhao, Lili ^{[5
]}

Narayanan, Ishwarya Venkata ^{[2
,4
]}

Magnuson, Brian ^{[5
]}

Gu, Yumei ^{[1
,2
]}

Yang, Jing ^{[1
,2
]}

Yi, Zhujun ^{[1
,2
]}

Babaniamansour, Sepideh ^{[1
,2
]}

Shameon, Sargis ^{[1
,2
]}

Xu, Chang ^{[1
,2
]}

Paulsen, Michelle T. ^{[2
,4
]}

Qiu, Ping ^{[6
]}

Jeyarajan, Sivakumar ^{[1
,2
]}

Ljungman, Mats ^{[2
,4
]}

Thomas, Dafydd ^{[1
,2
]}

Dou, Yali ^{[7
]}

Crawford, Howard ^{[8
]}

di Magliano, Marina Pasca ^{[9
]}

Ge, Kai ^{[10
]}

Yang, Bo

Shi, Jiaqi ^{[1
,2
,11
]}

机构：

[1] Univ Michigan, Rogel Canc Ctr, Dept Pathol & Clin Labs, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Ctr RNA Biomed, Ann Arbor, MI 48109 USA

[3] Cent South Univ, Xiangya Hosp 2, Changsha, Hunan, Peoples R China

[4] Univ Michigan, Rogel Canc Ctr, Dept Radiat Oncol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Dept Cardiac Surg, Ann Arbor, MI 48109 USA

[7] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA

[8] Henry Ford Pancreat Canc Ctr, Detroit, MI USA

[9] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA

[10] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA

[11] Univ Michigan, Rogel Canc Ctr, Dept Pathol, Ann Arbor, MI 48109 USA

来源：

INTERNATIONAL JOURNAL OF CANCER | 2023年 / 153卷 / 03期

基金：

美国国家卫生研究院;

关键词：

epithelial-mesenchymal transition; metastasis; miR-147b; MLL2; tumor suppressor; UP-REGULATION; SELF-RENEWAL; STEM-CELLS; EXPRESSION; MICRORNA; TUMOR; TUMORIGENICITY; HETEROGENEITY; SUBTYPES; PATTERNS;

D O I：

10.1002/ijc.34528

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-beta to the activin A pathway. We found that TGF-beta 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 tumorsuppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.

引用

页码：552 / 570

页数：19

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