Long non-coding RNA UCA1 desensitizes breast cancer cells to trastuzumab by impeding miR-18a repression of Yes-associated protein 1

Journal Article · Thu Feb 15 04:00:00 EST 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.02.006· OSTI ID:23137349

Zhu, Hua-yu ^[1]; Bai, Wen-dong ^[1]; Ye, Xing-ming ^[2]; Yang, An-gang ^[1]; Jia, Lin-tao ^[3]

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1. Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi (China)
2. Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian (China)
3. State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular, Biology, Fourth Military Medical University, Xi'an, Shaanxi (China)

Highlights: • Knockdown of UCA1 expression restored sensitivity of breast cancer cells to trastuzumab. • UCA1 knockdown upregulated miR-18a and downregulated YAP1 in breast cancer cells. • YAP1 is a direct target of miR-18a in breast cancer cells. • The UCA1/miR-18a/YAP1 feedback axis regulated the sensitivity of breast cancer cells to trastuzumab. Breast cancer resistance to the monoclonal erbB2/HER2 antibody trastuzumab (or herceptin) has become a significant obstacle in clinical targeted therapy of HER2-positive breast cancer. Previous research demonstrated that such drug resistance may be related to dysregulation of miRNA expression. Here, we found that knockdown of the long non-coding RNA, urothelial cancer associated 1 (UCA1), can promote the sensitivity of human breast cancer cells to trastuzumab. Mechanistically, UCA1 knockdown upregulated miR-18a and promoted miR-18a repression of Yes-associated protein 1 (YAP1). A luciferase reporter assay confirmed the association of miR-18a with wild-type UCA1 but not with UCA1 mutated at the predicted miR-18a-binding site. The direct targeting of YAP1 by miR-18a was verified by the observation that miR-18a mimic suppressed luciferase expression from a construct containing the YAP1 3′ untranslated region. Meanwhile, reciprocal repression of UCA1 and miR-18a were found to be Argonaute 2-dependent. Knockdown of YAP1 recapitulated the effect of UCA1 silencing by reducing the viability of trastuzumab-treated breast cancer cells, whereas inhibition of miR-18a abrogated UCA1 knockdown-induced improvement of trastuzumab sensitivity in breast cancer cells. These findings demonstrate that the UCA1/miR-18a/YAP1 axis plays an important role in regulating the sensitivity of breast cancer cells to trastuzumab, which has implications for the development of novel approaches to improving breast cancer responses to targeted therapy.

• OSTI ID: 23137349
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 496; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBODIES
DRUGS
LUCIFERASE
MAMMARY GLANDS
NEOPLASMS
RNA