Adiponectin deficiency promotes endometrial carcinoma pathogenesis and development via activation of mitogen‐activated protein kinase
- 24 January 2022
- journal article
- research article
- Published by Wiley in The Journal of Pathology
- Vol. 257 (2), 146-157
- https://doi.org/10.1002/path.5874
Abstract
Obesity is one of the major risk factors for cancer. Clinical studies have demonstrated that circulating levels of adiponectin are inversely correlated not only with the extent of adiposity, but also with the incidence of several types of cancer, chief among which is endometrial cancer (EC). However, thus far, adiponectin remains correlative factor, without definitive evidence to show a causal effect in EC and the potential mechanism(s) involved. To address this issue, we introduced an Apn-null mutation into Pten haploid deficient (Pten+/-) mice. Pten heterozygous mutation alone led to the development of EC in less than 30% of female mice; however, when combined with Apn-null mutation, the incidence of endometrial lesions rose to at least two-thirds. Although Apn deficiency did not further potentiate the Akt activation caused by Pten mutation, it elevated the phosphorylation of mitogen-activated protein kinase (MAPK) p42/44, indicating activation of the MAPK signaling pathway. Treatment of Apn-/-;Pten+/- mice with a MEK inhibitor blocked the development of EC. Finally, xenografts of a PTEN proficient human EC cell line grew faster in Apn-deficient mice, whilst an adiponectin receptor agonist reduced xenograft growth of a PTEN-deficient human EC cell line. Thus, reduction of adiponectin activity promotes EC development, at least in the context of Pten mutation, by activating MAPK.Funding Information
- Guangdong Province Introduction of Innovative R&D Team (2016ZT06Y432)
- National Natural Science Foundation of China (81630021)
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