The kinesin light chain‐2, a target of mRNA stabilizing protein HuR, inhibits p53 protein phosphorylation to promote radioresistance in NSCLC

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Abstract

Background

Radioresistance hinders radiotherapy for the treatment of lung cancer. Kinesin light chain‐2 (KLC2) has been found to be upregulated in lung cancer and also to be associated with poor prognosis. This study aimed to investigate the effect of KLC2 on radiosensitivity in lung cancer.

Methods

The radioresistant role of KLC2 was determined by colony formation, neutral comet assay, and γH2AX immunofluorescent staining assay. We further verified the function of KLC2 in a xenograft tumor model. The downstream of KLC2 was identified through gene set enrichment analysis and validated by western blot. Finally, we analyzed clinical data from the TCGA database to reveal the upstream transcription factor of KLC2, which was validated by RNA binding protein immunoprecipitation assay.

Results

Here, we found that downregulation of KLC2 could significantly reduce colony formation, increase γH2AX level, and double‐stranded DNA breaks in vitro. Meanwhile, overexpressed KLC2 significantly increased the proportion of the S phase in lung cancer cells. KLC2 knockdown could activate P53 pathway, and ultimately promoting radiosensitivity. The mRNA of KLC2 was observed to bind with Hu‐antigen R (HuR). The mRNA and protein expression of KLC2 in lung cancer cells was significantly reduced when combined with siRNA‐HuR. Interestingly, KLC2 overexpression significantly increased the expression of HuR in lung cancer cells.

Conclusion

Taken together, these results indicated that HuR‐KLC2 forms a positive feedback loop, which decreases the phosphorylation of p53 and thereby weaken the radiosensitivity of lung cancer cells. Our findings highlight the potential prognosis and therapeutic target value of KLC2 in lung cancer patients treated with radiotherapy.

Abstract

KLC2 is a downstream target of HuR, and they are required for radioresistance in NSCLC. The action mechanism of KLC2 involves p53 protein phosphorylation, thus promoting radioresistance.

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Most cited references 43

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Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

A. Subramanian, P. Tamayo, V. K. Mootha … (2005)

Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

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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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Cancer statistics, 2019

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2019)

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 cancer incidence, mortality, and survival. Incidence data, available through 2015, 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, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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Author and article information

Contributors

Xiaoxia Zhu:

ORCID: https://orcid.org/0000-0003-3030-0306

zhuxx01@126.com

Journal

Journal ID (nlm-ta): Thorac Cancer

Journal ID (iso-abbrev): Thorac Cancer

Journal ID (doi): 10.1111/(ISSN)1759-7714

Journal ID (publisher-id): TCA

Title: Thoracic Cancer

Publisher: John Wiley & Sons Australia, Ltd (Melbourne )

ISSN (Print): 1759-7706

ISSN (Electronic): 1759-7714

Publication date (Electronic): 13 April 2023

Publication date Collection: June 2023

Volume: 14

Issue: 16 ( doiID: 10.1111/tca.v14.16 )

Pages: 1440-1450

Affiliations

[ ¹ ] Department of Radiation Oncology Zhujiang Hospital, Southern Medical University Guangzhou China

Author notes

[*] [* ] Correspondence

Xiaoxia Zhu, Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Middle Avenue, Haizhu District, Guangzhou 510280, China.

Email: zhuxx01@ 123456126.com

Author information

Xiaoxia Zhu https://orcid.org/0000-0003-3030-0306

Article

Publisher ID: TCA14886

DOI: 10.1111/1759-7714.14886

PMC ID: 10234785

PubMed ID: 37055376

SO-VID: c0ab2eaa-b9ba-4a21-9272-92c60b205c8e

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date revision received : 23 March 2023

Date received : 01 March 2023

Date accepted : 24 March 2023

Page count

Figures: 5, Tables: 0, Pages: 11, Words: 6512

Funding

Funded by: Clinical Research Startup Program of Southern Medical University by High‐level University Construction Funding of Guangdong Provincial Department of Education

Award ID: LC2019ZD009

Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;

Award ID: 81972853

Award ID: 81902750

Custom metadata

source-schema-version-number 2.0

cover-date June 2023

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.8 mode:remove_FC converted:01.06.2023

Keywords: hur,kinesin light chain‐2,nsclc,p53,radioresistance

Data availability:

Keywords: hur, kinesin light chain‐2, nsclc, p53, radioresistance

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The kinesin light chain‐2, a target of mRNA stabilizing protein HuR, inhibits p53 protein phosphorylation to promote radioresistance in NSCLC

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Abstract

Background

Methods

Results

Conclusion

Abstract

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Journal of Circulating Biomarkers

Most cited references 43

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Cancer statistics, 2020

Cancer statistics, 2019

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Cited by 1

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