CircIL4R activates the PI3K/AKT signaling pathway via the miR-761/TRIM29/PHLPP1 axis and promotes proliferation and metastasis in colorectal cancer

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Abstract

Background

Accumulating studies have revealed that aberrant expression of circular RNAs (circRNAs) is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC). Nevertheless, the clinical significance, levels, features, biological function, and molecular mechanisms of novel circRNAs in CRC remain largely unexplored.

Methods

CRC-related circRNAs were identified through bioinformatics analysis and verified in clinical specimens by qRT–PCR and in situ hybridization (ISH). Then, in vitro and in vivo experiments were performed to determine the clinical significance of, functional roles of, and clinical characteristics associated with circIL4R in CRC specimens and cells. Mechanistically, RNA pull-down, fluorescence in situ hybridization (FISH), luciferase reporter, and ubiquitination assays were performed to confirm the underlying mechanism of circIL4R.

Results

CircIL4R was upregulated in CRC cell lines and in sera and tissues from CRC patients and was positively correlated with advanced clinicopathological features and poor prognosis. Functional experiments demonstrated that circIL4R promotes CRC cell proliferation, migration, and invasion via the PI3K/AKT signaling pathway. Mechanistically, circIL4R was regulated by TFAP2C and competitively interacted with miR-761 to enhance the expression of TRIM29, thereby targeting PHLPP1 for ubiquitin-mediated degradation to activate the PI3K/AKT signaling pathway and consequently facilitate CRC progression.

Conclusions

Our findings demonstrate that upregulation of circIL4R plays an oncogenic role in CRC progression and may serve as a promising diagnostic and prognostic biomarker for CRC detection and as a potential therapeutic target for CRC treatment.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12943-021-01474-9.

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Most cited references 54

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Cancer Statistics, 2021

Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2021)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.

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Colorectal cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ann Goding Sauer … (2020)

Colorectal cancer (CRC) is the second most common cause of cancer death in the United States. Every 3 years, the American Cancer Society provides an update of CRC occurrence based on incidence data (available through 2016) from population-based cancer registries and mortality data (through 2017) from the National Center for Health Statistics. In 2020, approximately 147,950 individuals will be diagnosed with CRC and 53,200 will die from the disease, including 17,930 cases and 3,640 deaths in individuals aged younger than 50 years. The incidence rate during 2012 through 2016 ranged from 30 (per 100,000 persons) in Asian/Pacific Islanders to 45.7 in blacks and 89 in Alaska Natives. Rapid declines in incidence among screening-aged individuals during the 2000s continued during 2011 through 2016 in those aged 65 years and older (by 3.3% annually) but reversed in those aged 50 to 64 years, among whom rates increased by 1% annually. Among individuals aged younger than 50 years, the incidence rate increased by approximately 2% annually for tumors in the proximal and distal colon, as well as the rectum, driven by trends in non-Hispanic whites. CRC death rates during 2008 through 2017 declined by 3% annually in individuals aged 65 years and older and by 0.6% annually in individuals aged 50 to 64 years while increasing by 1.3% annually in those aged younger than 50 years. Mortality declines among individuals aged 50 years and older were steepest among blacks, who also had the only decreasing trend among those aged younger than 50 years, and excluded American Indians/Alaska Natives, among whom rates remained stable. Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high-quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults.

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The biogenesis, biology and characterization of circular RNAs

Lasse S. Kristensen, Maria Andersen, Lotte V. W. Stagsted … (2019)

Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.

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Author and article information

Contributors

Renhao Wang:

ORCID: https://orcid.org/0000-0002-4465-9953

wangrenhao@xzhmu.edu.cn

Jun Song:

ORCID: http://orcid.org/0000-0002-6350-2695

songjun@xzhmu.edu.cn

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 18 December 2021

Publication date PMC-release: 18 December 2021

Publication date Collection: 2021

Volume: 20

Electronic Location Identifier: 167

Affiliations

[1 ]GRID grid.413389.4, ISNI 0000 0004 1758 1622, Department of General Surgery, , The Affiliated Hospital of Xuzhou Medical University, ; Xuzhou, 221006 Jiangsu China

[2 ]GRID grid.417303.2, ISNI 0000 0000 9927 0537, Institute of Digestive Diseases, Xuzhou Medical University, ; Xuzhou, 221002 Jiangsu China

[3 ]GRID grid.417303.2, ISNI 0000 0000 9927 0537, The Graduate School, , Xuzhou Medical University, ; Xuzhou, 221004 Jiangsu China

[4 ]GRID grid.419611.a, ISNI 0000 0004 0457 9072, State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, , Beijing Institute of Lifeomics, ; Beijing, China

Author information

Renhao Wang https://orcid.org/0000-0002-4465-9953

Jun Song http://orcid.org/0000-0002-6350-2695

Article

Publisher ID: 1474

DOI: 10.1186/s12943-021-01474-9

PMC ID: 8684286

PubMed ID: 34922544

SO-VID: 041e7865-fd6d-41e1-a05f-ea017562c60f

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 27 August 2021

Date accepted : 1 December 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82073133

Award Recipient : Jun Song

Funded by: FundRef http://dx.doi.org/10.13039/501100010854, Jiangsu Provincial Commission of Health and Family Planning;

Award ID: ZDA2020005

Award Recipient : Jun Song

Funded by: FundRef http://dx.doi.org/10.13039/501100004608, Natural Science Foundation of Jiangsu Province;

Award ID: BK20191154

Award Recipient : Jun Song

Funded by: FundRef http://dx.doi.org/10.13039/501100010014, Six Talent Peaks Project in Jiangsu Province;

Award ID: WSW-050

Award Recipient : Jun Song

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: circil4r,mir-761,trim29,pi3k/akt pathway,colorectal cancer

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: circil4r, mir-761, trim29, pi3k/akt pathway, colorectal cancer

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CircIL4R activates the PI3K/AKT signaling pathway via the miR-761/TRIM29/PHLPP1 axis and promotes proliferation and metastasis in colorectal cancer

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Karger: Oncology

Most cited references 54

Cancer Statistics, 2021

Colorectal cancer statistics, 2020

The biogenesis, biology and characterization of circular RNAs

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Contributors

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Cited by 36

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