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Validation of ZMYND8 as a new treatment target in hepatocellular carcinoma

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

ZMYND8 (Zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8) has been known to play an important role in tumor regulation in various types of cancer. However, the results of ZMYND8 expression and their clinical significance in hepatocellular carcinoma (HCC) have not yet been published. In the present study, we investigate the expression of ZMYND8 protein and mRNA in HCC and elucidate its prognostic significance.

Methods

ZMYND8 protein and mRNA expression in 283 and 234 HCCs were investigated using immunohistochemistry and microarray gene expression profiling data. The relationships between ZMYND8 expression with clinicopathologic features and prognosis of HCC patients were evaluated. Furthermore, we performed the invasion, migration, apoptosis, soft agar formation assay and sphere formation assay in HCC cell lines, and evaluated tumorigenicity in a nude mouse model, after ZMYND8 knockdown.

Results

Overexpression of ZMYND8 protein and mRNA was observed in 20.5% and 26.9% of HCC cases, respectively. High ZMYND8 expression showed significant correlations with microvascular invasion, high Edmondson grade, advanced American Joint Committee on Cancer, and increased alpha-fetoprotein level. ZMYND8 mRNA overexpression was an independent prognostic factor for predicting early recurrence as well as short recurrence-free survival (RFS). Downregulation of ZMYND8 reduced migration and invasion of HCC cells, and promoted apoptosis of HCC cells in an in vitro model. In a xenograft nude mouse model, knockdown of ZMYND8 significantly reduced tumor growth.

Conclusion

ZMYND8 mRNA overexpression could be a prognostic marker of shorter RFS in HCC patients after curative resection. ZMYND8 might play an important role in the proliferation and progression of HCC and could be a promising candidate for targeted therapy.

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Availability of data and materials

All datasets used and analyzed during this study are available from the corresponding author on reasonable request.

Abbreviations

HCC:

Hepatocellular carcinoma

ZMYND8:

Zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8

HIF:

Hypoxia-inducible factor

ER:

Estrogen receptor

AFP:

α-Fetoprotein

HPFs:

High-power fields

AJCC:

American Joint Committee on Cancer

BCLC:

Barcelona Clinic Liver Cancer

RFS:

Recurrence-free survival

DSS:

Disease-specific survival

IHC:

Immunohistochemistry

DEG:

Differentially expressed genes

FDR:

False Discovery Rate

TCGA:

The Cancer Genome Atlas

GEPIA:

Gene Expression Profiling Interactive Analysis

shRNA:

Short hairpin RNA

RACK:

Receptor for activated C-kinase

PKCβ1:

Protein-kinase-C beta I

ATRA:

All-trans retinoic acid

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Funding

This study was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017R1C1B5017890 and NRF-2018R1C1B6006428).

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Author notes

  1. Sangjoon Choi and Keun-Woo Lee contributed equally in this study.

Authors and Affiliations

  1. Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea

    Sangjoon Choi, Hyun Hee Koh, Sujin Park, Seok-Hyung Kim, Cheol-Keun Park & Sang Yun Ha

  2. Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea

    Keun-Woo Lee, So-Young Yeo & Seok-Hyung Kim

  3. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Jae-Won Joh

  4. Department of Internal Medicine (Division of Gastroenterology), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Moon Seok Choi

  5. Department of Pathology, Anatomic Pathology Reference Lab, Seegene Medical Foundation, Seoul, Republic of Korea

    Cheol-Keun Park

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  1. Sangjoon Choi
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Contributions

SC performed data analysis, generated tables and figures, and drafted the manuscript. KWL performed in vitro and in vivo assays, analyzed the data and drafted the manuscript. HHK analyzed data. SP, SYY, JWJ, MSC supported data acquisition. SHK and CKP contributed to knowledge. SYH conceptualized and designed the study, collected and analyzed the data, drafted and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Sang Yun Ha.

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All contributing authors have no financial support relevant to this article and no competing interests to declare.

Ethical approval and consent to participate

The Institutional Review Board of Samsung Medical Center approved this study and waived informed consent for this study.

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All authors agreed to publish the article.

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Choi, S., Lee, KW., Koh, H.H. et al. Validation of ZMYND8 as a new treatment target in hepatocellular carcinoma. J Cancer Res Clin Oncol 147, 3517–3534 (2021). https://doi.org/10.1007/s00432-021-03768-3

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  • DOI: https://doi.org/10.1007/s00432-021-03768-3

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