Lysophosphatidic acid-induced amphiregulin secretion by cancer-associated fibroblasts augments cancer cell invasion

Bo Young Jeong, Kyung Hwa Cho, Kang Jin Jeong, Su Jin Cho, Minho Won, Seung Hwa Kim, Nam Hoon Cho, Gang Min Hur, Se Hee Yoon, Hwan Woo Park, Gordon B. Mills, Hoi Young Lee

Research output: Contribution to journalArticlepeer-review


Cancer-associated fibroblasts (CAFs) are key structural components of the tumor microenvironment and are closely associated with tumor invasion and metastasis. Lysophosphatidic acid (LPA) is a biolipid produced extracellularly and involved in tumorigenesis and metastasis. LPA has recently been implicated in the education and transdifferentiation of normal fibroblasts (NFs) into CAFs. However, little is known about the effects of LPA on CAFs and their participation in cancer cell invasion. In the present study, we identified a critical role of LPA-induced amphiregulin (AREG) secreted from CAFs in cancer invasiveness. CAFs secrete higher amounts of AREG than NFs, and LPA induces AREG expression in CAFs to augment their invasiveness. Strikingly, knocking out the AREG gene in CAFs attenuates cancer invasiveness and metastasis. Mechanistically, LPA induces Yes-associated protein (YAP) activation and Zinc finger E-box binding homeobox 1 (Zeb1) expression through the LPAR1 and LPAR3/Gi/Rho signaling axes, leading to AREG expression. Furthermore, we provide evidence that metformin, a biguanide derivative, significantly inhibits LPA-induced AREG expression in CAFs to attenuate cancer cell invasiveness. Collectively, the present data show that LPA induces AREG expression through YAP and Zeb1 in CAFs to promote cancer cell invasiveness, with the process being inhibited by metformin, providing potential biomarkers and therapeutic avenues to interdict cancer cell invasion.

Original languageEnglish
Article number215946
JournalCancer Letters
Publication statusPublished - 2022 Nov 28

Bibliographical note

Funding Information:
This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) , the Ministry of Science and ICT, Republic of Korea ( NRF-2017R1E1A1A01074091 and NRF-2022R1A2C1004019 ).

Publisher Copyright:
© 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


Dive into the research topics of 'Lysophosphatidic acid-induced amphiregulin secretion by cancer-associated fibroblasts augments cancer cell invasion'. Together they form a unique fingerprint.

Cite this