Elevated Expression of ASXL2 is Associated with Poor Prognosis in Colorectal Cancer by Enhancing Tumorigenesis and Inducing Cell Proliferation

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Abstract

Objective

Colorectal cancer is one of the most common malignant tumors worldwide. ASXL2 is an enhancer of the trithorax and polycomb genes, which have been proven to act in many tumor types. The role of ASXL2 in the occurrence and development of tumors has been extensively studied in recent years. However, the relationship between ASXL2 and the prognosis of CRC is still unclear.

Materials and Methods

In this study, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis and immunohistochemistry (IHC) were used to examine the expression of ASXL2 in CRC tissues. Cells were transfected with siRNAs or lentivirus to regulate the expression of ASXL2. The effects of ASXL2 on the proliferation of CRC cells were determined by CCK8 assay.

Results

This study demonstrated that ASXL2 was significantly more highly expressed in CRC specimens than in normal adjacent tissues. The upregulation of ASXL2 was related to advanced clinical stage. Patients who exhibited high expression levels of ASXL2 had poorer overall survival, whereas those with low expression of ASXL2 survived longer. Multivariate Cox regression analysis revealed that ASXL2 expression could be considered an independent prognostic factor for CRC. Inhibition or overexpression of ASXL2 markedly influenced the proliferation of CRC cells.

Conclusion

These results showed that ASXL2 could induce cell proliferation, which was associated with poor prognosis of CRC patients, suggesting that ASXL2 might be a new therapeutic target for CRC.

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Most cited references 25

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Cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) 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 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.

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The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging.

Mahul B Amin, Frederick Greene, Stephen Edge … (2017)

The American Joint Committee on Cancer (AJCC) staging manual has become the benchmark for classifying patients with cancer, defining prognosis, and determining the best treatment approaches. Many view the primary role of the tumor, lymph node, metastasis (TNM) system as that of a standardized classification system for evaluating cancer at a population level in terms of the extent of disease, both at initial presentation and after surgical treatment, and the overall impact of improvements in cancer treatment. The rapid evolution of knowledge in cancer biology and the discovery and validation of biologic factors that predict cancer outcome and response to treatment with better accuracy have led some cancer experts to question the utility of a TNM-based approach in clinical care at an individualized patient level. In the Eighth Edition of the AJCC Cancer Staging Manual, the goal of including relevant, nonanatomic (including molecular) factors has been foremost, although changes are made only when there is strong evidence for inclusion. The editorial board viewed this iteration as a proactive effort to continue to build the important bridge from a "population-based" to a more "personalized" approach to patient classification, one that forms the conceptual framework and foundation of cancer staging in the era of precision molecular oncology. The AJCC promulgates best staging practices through each new edition in an effort to provide cancer care providers with a powerful, knowledge-based resource for the battle against cancer. In this commentary, the authors highlight the overall organizational and structural changes as well as "what's new" in the Eighth Edition. It is hoped that this information will provide the reader with a better understanding of the rationale behind the aggregate proposed changes and the exciting developments in the upcoming edition. CA Cancer J Clin 2017;67:93-99. © 2017 American Cancer Society.

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The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer

Catherine S. Grasso, Yi-Mi Wu, Dan R Robinson … (2012)

Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC) 1 . As less is known about the role of mutations 2–4 , here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS fusionnegative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR-mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signaling and increases tumour growth. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Manag Res

Journal ID (iso-abbrev): Cancer Manag Res

Journal ID (publisher-id): cmar

Journal ID (pmc): cancmanres

Title: Cancer Management and Research

Publisher: Dove

ISSN (Electronic): 1179-1322

Publication date (Electronic): 19 October 2020

Publication date Collection: 2020

Volume: 12

Pages: 10221-10228

Affiliations

[1 ]Department of Hepatopancreatobiliary Surgery, East Hospital Affiliated Tongji University, Tongji University School of Medicine , Shanghai 200120, People’s Republic of China

[2 ]State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University , Shanghai 200240, People’s Republic of China

[3 ]Department of Gastrointestinal Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, 200127, People’s Republic of China

Author notes

Correspondence: Bo Chen Department of Hepatopancreatobiliary Surgery, East Hospital Affiliated Tongji University, Tongji University School of Medicine , 1800 Yuntai Road, Shanghai, People’s Republic of China Email chenbo7349@sohu.com

Minhao Yu Department of Gastrointestinal Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine , 160 Pujian Road, Shanghai, People’s Republic of China Email fishmeangood@163.com

[*]

These authors contributed equally to this work

Author information

Yiwei Wang http://orcid.org/0000-0003-1314-1833

Article

Publisher ID: 266083

DOI: 10.2147/CMAR.S266083

PMC ID: 7585280

PubMed ID: 33116876

SO-VID: 038f1aaa-53cd-489b-a5eb-6896bbc1aa8a

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 10 June 2020

Date accepted : 21 September 2020

Page count

Figures: 4, Tables: 5, References: 25, Pages: 8

Funding

Funded by: the National Natural Science Foundation of China;

Funded by: The Outstanding Clinical Discipline Project of Shanghai Pudong;

Funded by: The Research project of Shanghai Municipal Health Commission;

This work was supported by the grant from the National Natural Science Foundation of China (No. 81702300), The Outstanding Clinical Discipline Project of Shanghai Pudong (No. PWYgy2018-02) and The Research project of Shanghai Municipal Health Commission (No. 20204Y0302).

Elevated Expression of ASXL2 is Associated with Poor Prognosis in Colorectal Cancer by Enhancing Tumorigenesis and Inducing Cell Proliferation

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Abstract

Objective

Materials and Methods

Results

Conclusion

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Karger: Oncology

Most cited references 25

Cancer statistics, 2020

The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging.

The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer

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