Long Noncoding RNA HCG18 Promotes Malignant Phenotypes of Breast Cancer Cells via the HCG18/miR-103a-3p/UBE2O/mTORC1/HIF-1α-Positive Feedback Loop

Xu Liu; Kun Qiao; Kaiyuan Zhu; Xianglan Li; Chunbo Zhao; Jiaqi Li; Dawei Feng; Yu Fang; Peng Wang; Cheng Qian; Wenbo Qiao

doi:10.3389/fcell.2021.675082

Long Noncoding RNA HCG18 Promotes Malignant Phenotypes of Breast Cancer Cells via the HCG18/miR-103a-3p/UBE2O/mTORC1/HIF-1α-Positive Feedback Loop

Front Cell Dev Biol. 2021 Dec 7:9:675082. doi: 10.3389/fcell.2021.675082. eCollection 2021.

Authors

Xu Liu¹, Kun Qiao², Kaiyuan Zhu², Xianglan Li¹, Chunbo Zhao¹, Jiaqi Li¹, Dawei Feng³, Yu Fang⁴, Peng Wang¹, Cheng Qian², Wenbo Qiao¹

Affiliations

¹ Department of Abdominal Radiotherapy, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China.
² Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China.
³ Department of Radiotherapy Technology Center, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China.
⁴ Department of Oncology Phase I Clinical Research, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China.

Abstract

In recent years, an increasing number of studies have reported that long noncoding RNAs (lncRNAs) play crucial roles in breast cancer (BC) progression and metastasis. Another study group of our research center reported that lncRNA HCG18 was one of the 30 upregulated lncRNAs in BC tissues compared with normal tissues in The Cancer Genome Atlas database. However, the exact biological roles of HCG18 in BC remain unclear. In this study, we demonstrated that HCG18 is significantly upregulated in BC tissues and cells and that BC patients with high HCG18 expression tend to have poor prognosis. In vitro assays indicated that HCG18 promotes BC cell proliferation and invasion and endows BC cells with cancer stemness properties. In vivo assays revealed that reducing HCG18 expression in the BC cell line MDA-MB-231 markedly decreased tumor growth and lung metastasis in xenograft mouse models. In terms of mechanism, we found that HCG18 positively regulated the expression of BC-related ubiquitin-conjugating enzyme E2O (UBE2O) by sponging miR-103a-3p, and our previous research verified that UBE2O could promote the malignant phenotypes of BC cells through the UBE2O/AMPKα2/mTORC1 axis. Furthermore, as a downstream target of the HCG18/miR-103a-3p/UBE2O/mTORC1 axis, hypoxia-inducible factor 1α transcriptionally promoted HCG18 expression and then formed a positive feedback loop in BC. Taken together, these results confirm that HCG18 plays an oncogenic role in BC and might serve as a prognostic biomarker and a potential therapeutic target for BC treatment.

Keywords: HCG18; MiR-103a-3p; UBE2O; breast cancer; mechanistic target of rapamycin complex 1.