CDCA8 induced by NF-YA promotes hepatocellular carcinoma progression by regulating the MEK/ERK pathway

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Abstract

Background

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors. Cell division cycle associated 8 (CDCA8) is an important multifactorial regulator in cancers. However, its up and downstream targets and effects in HCC are still unclear.

Methods

A comprehensive bioinformatics analysis was performed using The Cancer Genome Atlas dataset (TCGA) to explore novel core oncogenes. We quantified CDCA8 levels in HCC tumors using qRT-PCR. HCC cell’s proliferative, migratory, and invasive abilities were detected using a Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2′-deoxyuridine (EdU) assay, clone formation, and a Transwell assay. An orthotopic tumor model and tail vein model were constructed to determine the effects of CDCA8 inhibition in vivo. The mechanism underlying CDCA8 was investigated using RNA sequencing. The prognostic value of CDCA8 was assessed with immunohistochemical staining of the tissue microarrays.

Results

CDCA8 was identified as a novel oncogene during HCC development. The high expression of CDCA8 was an independent predictor for worse HCC outcomes both in publicly available datasets and in our cohort. We found that CDCA8 knockdown inhibited HCC cell proliferation, colony formation, and migration by suppressing the MEK/ERK pathway in vitro. Moreover, CDCA8 deficiency significantly inhibited tumorigenesis and metastasis. Next-generation sequencing and laboratory validation showed that CDCA8 silencing inhibited the expression of TPM3, NECAP2, and USP13. Furthermore, NA-YA overexpression upregulated the expression of CDCA8. CDCA8 knockdown could attenuate NF-YA-mediated cell invasion in vitro. The expression of NF-YA alone or in combined with CDCA8 were validated as significant independent risk factors for patient survival.

Conclusion

Our findings revealed that the expression of CDCA8 alone or in combined with NF-YA contributed to cancer progression, and could serve as novel potential therapeutic targets for HCC patients.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40164-022-00366-y.

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Most cited references 43

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Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

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Douglas Hanahan, Robert A. Weinberg (2011)

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

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GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses

Zefang Tang, Chenwei Li, Boxi Kang … (2017)

Abstract Tremendous amount of RNA sequencing data have been produced by large consortium projects such as TCGA and GTEx, creating new opportunities for data mining and deeper understanding of gene functions. While certain existing web servers are valuable and widely used, many expression analysis functions needed by experimental biologists are still not adequately addressed by these tools. We introduce GEPIA (Gene Expression Profiling Interactive Analysis), a web-based tool to deliver fast and customizable functionalities based on TCGA and GTEx data. GEPIA provides key interactive and customizable functions including differential expression analysis, profiling plotting, correlation analysis, patient survival analysis, similar gene detection and dimensionality reduction analysis. The comprehensive expression analyses with simple clicking through GEPIA greatly facilitate data mining in wide research areas, scientific discussion and the therapeutic discovery process. GEPIA fills in the gap between cancer genomics big data and the delivery of integrated information to end users, thus helping unleash the value of the current data resources. GEPIA is available at http://gepia.cancer-pku.cn/.

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Author and article information

Contributors

Yi Lu: luy3@sustech.edu.cn

Jikui Liu: liu8929@126.com

Jian Zhang: zhangjian@sustech.edu.cn

Journal

Journal ID (nlm-ta): Exp Hematol Oncol

Journal ID (iso-abbrev): Exp Hematol Oncol

Title: Experimental Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 2162-3619

Publication date (Electronic): 13 January 2023

Publication date PMC-release: 13 January 2023

Publication date Collection: 2023

Volume: 12

Electronic Location Identifier: 9

Affiliations

[1 ]GRID grid.440601.7, ISNI 0000 0004 1798 0578, Department of Hepatobiliary and Pancreatic Surgery, , Peking University Shenzhen Hospital, ; Shenzhen, 518036 Guangdong China

[2 ]GRID grid.263817.9, ISNI 0000 0004 1773 1790, School of Medicine, , Southern University of Science and Technology, ; Shenzhen, 518055 Guangdong China

[3 ]GRID grid.440601.7, ISNI 0000 0004 1798 0578, Department of Pathology, , Peking University Shenzhen Hospital, ; Shenzhen, Guangdong China

[4 ]GRID grid.414701.7, Department of Ophthalmology, , Affiliated Eye Hospital of Wenzhou Medical University, ; Wenzhou, Zhejiang China

[5 ]Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, Guangdong China

Article

Publisher ID: 366

DOI: 10.1186/s40164-022-00366-y

PMC ID: 9838039

PubMed ID: 36639822

SO-VID: 757511a0-934e-41bf-ac67-9094da30d20c

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 : 4 May 2022

Date accepted : 29 December 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002858, China Postdoctoral Science Foundation;

Award ID: 2020M682779

Award Recipient : Erbao Chen

Funded by: FundRef http://dx.doi.org/10.13039/501100010877, Science, Technology and Innovation Commission of Shenzhen Municipality;

Award ID: JCYJ20190809095801653

Award ID: JCYJ20170412154619484

Award ID: JCYJ20190809100217290

Award ID: JCYJ20190809161811237

Award Recipient : Zewei Lin Yi Lu Jikui Liu Jian Zhang

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

Award ID: 81972420

Award ID: 81972766

Award Recipient : Yi Lu Jian Zhang

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma,cell division cycle associated 8,nf-ya,cancer metastasis,prognosis

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma, cell division cycle associated 8, nf-ya, cancer metastasis, prognosis

CDCA8 induced by NF-YA promotes hepatocellular carcinoma progression by regulating the MEK/ERK pathway

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Supplementary Information

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Karger: Oncology

Most cited references 43

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Hallmarks of Cancer: The Next Generation

GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses

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