MiR‑221 and miR‑222 regulate cell cycle progression and affect chemosensitivity in breast cancer by targeting ANXA3

Ju-Yeon Kim; Eun Jung Jung; Jae-Myung Kim; Youngsim Son; Han Shine Lee; Seung-Jin Kwag; Ji-Ho Park; Jin-Kyu Cho; Han-Gil Kim; Taejin Park; Sang-Ho Jeong; Chi-Young Jeong; Young-Tae Ju

doi:10.3892/etm.2023.11826

MiR‑221 and miR‑222 regulate cell cycle progression and affect chemosensitivity in breast cancer by targeting ANXA3

Exp Ther Med. 2023 Feb 7;25(3):127. doi: 10.3892/etm.2023.11826. eCollection 2023 Mar.

Authors

Affiliations

¹ Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea.
² Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang 51472, Republic of Korea.

Abstract

Breast malignancy remains one of the most common causes of cancer-associated mortalities among women. MicroRNA (miR)-221 and miR-222 are homologous miRs and have a substantial impact on cancer progression. In the present study, the regulatory mechanisms of miR-221/222 and its target annexin A3 (ANXA3) in breast cancer cells were investigated. Breast tissue samples were collected to evaluate the expression patterns of miR-221/222 levels in breast cancer cell lines and cancer tissues according to clinical characteristics. The levels of miR-221/222 were increased or decreased in cancer cell lines compared with normal breast cell lines according to cell line subtype. Subsequently, the changes in the progression and invasion of breast cancer cells were investigated using cell proliferation, invasion assay, gap closure and colony formation assays. Western blotting of cell cycle proteins and flow cytometry were performed to evaluate the possible pathway of miR-221/222 and ANXA3 axis. Chemosensitivity tests were performed to explore the suitability of the miR-221/222 and ANXA3 axis as a therapeutic target in breast cancer. The expression levels of miR-221/222 were associated with aggressive characteristics of breast cancer subtypes. Cell transfection assay demonstrated the regulation of breast cancer proliferation and invasiveness by miR-221/222. MiR-221/222 directly targeted the 3'-untranslated region of ANXA3 and suppressed the expression of ANXA3 at the mRNA and protein levels. In addition, miR-221/222 negatively regulated cell proliferation and the cell cycle pathway in breast cancer cells by targeting ANXA3. In combination with adriamycin, downregulation of ANXA3 may sensitize adriamycin-induced cell death to induction of persistent G₂/M and G₀/G₁ arrest. Decreased expression of ANXA3 through increased expression of miR-221/222 reduced breast cancer progression and increased the effectiveness of the chemotherapy drug. The present results indicated the miR-221/222 and ANXA3 axis to be a possible novel therapeutic target for the treatment of breast cancer.

Keywords: annexin A3; breast neoplasm; chemotherapy; microRNA-221; microRNA-222.

Grants and funding

Funding: The present study was supported by The Biomedical Research Institute Fund of Gyeongsang National University Hospital (grant no. GNUHBRIF-2019-0010) and a National Research Foundation of Korea grant sponsored by the Korean government (grant nos. NRF-2019R1F1A1057175 and NRF-2017R1D1A1B03034183).