bims-micpro 2021-03-07 papers

Issue of 2021‒03‒07
two papers selected by
Thomas Martinez
Salk Institute for Biological Studies

Nat Cell Biol. 2021 Mar 04.

Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling.

Xinya Gao, Xin Xia, Fanying Li, Maolei Zhang, Huangkai Zhou, Xujia Wu, Jian Zhong, Zheng Zhao, Kun Zhao, Dawei Liu, Feizhe Xiao, Qiang Xu, Tao Jiang, Bo Li, Shi-Yuan Cheng, Nu Zhang.

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.

DOI: https://doi.org/10.1038/s41556-021-00639-4

Mitochondrion. 2021 Feb 24. pii: S1567-7249(21)00017-9. [Epub ahead of print]

The mitochondrial-derived peptide MOTS-c promotes homeostasis in aged human placenta-derived mesenchymal stem cells in vitro.

Won Dong Yu, Yu Jin Kim, Min Jeong Cho, Jin Seok, Jung Jae Ko, Gi Jin Kim, Chang-Han Lee, You Shin Kim, Jae Ho Lee.

Mesenchymal stem cells (MSCs) are multipotent cells with critical roles in homeostasis and regeneration. MSCs undergo aging in response to various stresses, and this causes many diseases including degenerative disorders. Thus, regulation of aging factors is crucial for healthy aging. Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) was recently reported to regulate metabolic homeostasis. Here, we investigated the restorative effects of MOTS-c on aged human placenta-derived MSCs (hPD-MSCs). MOTS-c promoted the morphology of old hPD-MSCs. MOTS-c significantly activated AMP-activated protein kinase, which is the main target pathway of MOTS-c, and inhibited its antagonistic effector mTORC1. MOTS-c considerably enhanced mitochondrial homeostasis by decreasing oxygen consumption and reactive oxygen species production. The mitochondrial state of MOTS-c-treated old hPD-MSCs was more similar to that of young hPD-MSCs than the mitochondrial state of non-treated old hPD-MSCs. MOTS-c also decreased lipid synthesis. In conclusion, we demonstrated that MOTS-c promotes homeostasis in aged hPD-MSCs.

Keywords: AMPK; Aging; Homeostasis; MOTS-c; MSC; Mitochondria

DOI: https://doi.org/10.1016/j.mito.2021.02.010