CCDC85A is regulated by miR-224-3p and augments cancer cell resistance to endoplasmic reticulum stress

So Takahashi; Kurara Takagane; Go Itoh; Sei Kuriyama; Michinobu Umakoshi; Akiteru Goto; Kazuyoshi Yanagihara; Masakazu Yashiro; Katsunori Iijima; Masamitsu Tanaka

doi:10.3389/fonc.2023.1196546

CCDC85A is regulated by miR-224-3p and augments cancer cell resistance to endoplasmic reticulum stress

Front Oncol. 2023 Jul 18:13:1196546. doi: 10.3389/fonc.2023.1196546. eCollection 2023.

Authors

Affiliations

¹ Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
² Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan.
³ Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, Akita, Japan.
⁴ Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan.
⁵ Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Abstract

MicroRNAs (miRNAs) play pivotal roles in the tumor microenvironment. Here, we analyzed miRNAs in tumor stromal fibroblasts. Expression of miR-224-3p in cancer-associated fibroblasts (CAF) from scirrhous gastric cancer patients was lower than in normal fibroblasts (NF). Introduction of a miR-224-3p mimic attenuated migration and invasion of CAF. Coiled-coil domain containing 85A (CCDC85A), whose function in tumors is not understood, was the target gene of miR-224-3p. Immunohistological analysis revealed that CCDC85A is expressed to varying degrees by cancer cells and CAFs in gastric and pancreatic carcinomas. Downregulation of CCDC85A in cancer cells revealed that these cells are vulnerable to endoplasmic reticulum (ER) stress induced by thapsigargin or tunicamycin, which were ameliorated after addback of CCDC85A. Injection of NF-derived exosomes containing miR-224-3p into the xenograft tumor increased tumor shrinkage by cisplatin treatment. Mechanistically, CCDC85A associated with the molecular chaperone GRP78 and GRP94, thereby inhibiting association of these negative regulators of the unfolded protein response (UPR), leading to sustained activation of PERK and downstream eIF2〈 and ATF4 upon ER stress. These data suggest a novel miR-224-3p-mediated function for CCDC85A: protection from ER stress and cisplatin resistance.

Keywords: CCDC85A; ER stress; cisplatin resistance; exosomes; miR224-3p.

Grants and funding

This work was supported by JSPS KAKENHI grants (22H02897 to MT, 22K07163 to GI, 21K07090 to SK, and 22H04373 to KT), Takeda Science Foundation grants (to MT and GI), and a Research Grant from the Princess Takamatsu Cancer Research Fund (19-25123 to MT).