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Molecular Cancer
Published in: Molecular Cancer 1/2024

Open Access 01-12-2024 | Colorectal Cancer | Research

CircHAS2 activates CCNE2 to promote cell proliferation and sensitizes the response of colorectal cancer to anlotinib

Authors: Haosheng Li, Haoran Feng, Tao Zhang, Junwei Wu, Xiaonan Shen, Shuiyu Xu, Lianghui Xu, Shaodong Wang, Yaqi Zhang, Wenqing Jia, Xiaopin Ji, Xi Cheng, Ren Zhao

Published in: Molecular Cancer | Issue 1/2024

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Abstract

Background

Tyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure.

Methods

The whole transcriptome RNA sequencing and function experiments were conducted to identify candidate anlotinib-regulated circRNAs, whose mechanism was confirmed by molecular biology experiments. CircHAS2 was profiled in a library of patient-derived CRC organoids (n = 22) and patient-derived CRC tumors in mice. Furthermore, a prospective phase II clinical study of 14 advanced CRC patients with anlotinib-based therapy was commenced to verify drug sensitivity (ClinicalTrials.gov identifier: NCT05262335).

Results

Anlotinib inhibits tumor growth in vitro and in vivo by downregulating circHAS2. CircHAS2 modulates CCNE2 activation by acting as a sponge for miR-1244, and binding to USP10 to facilitate p53 nuclear export as well as degradation. In parallel, circHAS2 serves as a potent biomarker predictive of anlotinib sensitivity, both in patient-derived organoids and xenograft models. Moreover, the efficacy of anlotinib inclusion into the treatment regimen yields meaningful clinical responses in patients with high levels of circHAS2. Our findings offer a promising targeted strategy for approximately 52.9% of advanced CRC patients who have high circHAS2 levels.

Conclusions

CircHAS2 promotes cell proliferation via the miR-1244/CCNE2 and USP10/p53/CCNE2 bidirectional axes. Patient-derived organoids and xenograft models are employed to validate the sensitivity to anlotinib. Furthermore, our preliminary Phase II clinical study, involving advanced CRC patients treated with anlotinib, confirmed circHAS2 as a potential sensitivity marker.
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Metadata
Title
CircHAS2 activates CCNE2 to promote cell proliferation and sensitizes the response of colorectal cancer to anlotinib
Authors
Haosheng Li
Haoran Feng
Tao Zhang
Junwei Wu
Xiaonan Shen
Shuiyu Xu
Lianghui Xu
Shaodong Wang
Yaqi Zhang
Wenqing Jia
Xiaopin Ji
Xi Cheng
Ren Zhao
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2024
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-024-01971-7

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