Jeong Bo Young, Cho Kyung Hwa, Jeong Kang Jin, Cho Su Jin, Won Minho, Kim Seung Hwa, Cho Nam Hoon, Hur Gang Min, Yoon Se-Hee, Park Hwan-Woo, Mills Gordon B, Lee Hoi Young
Department of Pharmacology, College of Medicine, Konyang University, Daejeon, 35365, Republic of Korea; Division of Oncological Sciences Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 97201, USA.
Department of Pharmacology, College of Medicine, Konyang University, Daejeon, 35365, Republic of Korea.
Cancer Lett. 2022 Dec 28;551:215946. doi: 10.1016/j.canlet.2022.215946. Epub 2022 Oct 7.
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.
癌症相关成纤维细胞（CAFs）是肿瘤微环境的关键结构成分，与肿瘤侵袭和转移密切相关。溶血磷脂酸（LPA）是一种在细胞外产生的生物脂质，参与肿瘤发生和转移。最近有研究表明，LPA与正常成纤维细胞（NFs）向CAFs的转化及转分化有关。然而，关于LPA对CAFs的影响及其在癌细胞侵袭中的作用，人们了解甚少。在本研究中，我们发现CAFs分泌的LPA诱导的双调蛋白（AREG）在癌症侵袭中起关键作用。CAFs分泌的AREG量高于NFs，LPA诱导CAFs中AREG表达以增强其侵袭性。令人惊讶的是，敲除CAFs中的AREG基因可减弱癌症侵袭和转移。机制上，LPA通过LPAR1和LPAR3/Gi/Rho信号轴诱导Yes相关蛋白（YAP）激活和锌指E盒结合同源框1（Zeb1）表达，从而导致AREG表达。此外，我们提供的证据表明，双胍衍生物二甲双胍可显著抑制LPA诱导的CAFs中AREG表达，从而减弱癌细胞侵袭性。总体而言，本研究数据表明，LPA通过YAP和Zeb1诱导CAFs中AREG表达以促进癌细胞侵袭，而该过程受到二甲双胍的抑制，这为阻断癌细胞侵袭提供了潜在的生物标志物和治疗途径。
