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MicroRNA miR-29a Inhibits Colon Cancer Progression by Downregulating B7-H3 Expression: Potential Molecular Targets for Colon Cancer Therapy

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Abstract

MiR-29a belongs to one of the subtypes of miRNAs known as non-coding single-stranded RNAs and is preferentially expressed in normal tissues. B7-H3, a member of the B7/CD28 immunoglobulin superfamily, was shown to be overexpressed in several solid malignant tumors, including colon cancer. In addition, it is associated with tumor progression and poor prognosis. We used immunohistochemical and Western blotting to assess B7-H3 protein expression levels in colon cancer and adjacent normal tissues and then compared their relationships with clinicopathological factors. Quantitative real-time reverse-transcription PCR was used to assess B7-H3 and miRNA-29a mRNA expression levels, and then their relationship and clinical significance were evaluated. In addition, colon cancer Caco-2 cells, which constitutively overexpress B7-H3, were transfected with lentivirus particles for miR-29a upregulation. Invasion and migration assays were carried out in vitro along with the establishment of a subcutaneous xenograft model in vivo to determine the role of miRNA-29a in colon cancer progression. The B7-H3 protein showed elevated expression in colon carcinoma and was relevant to TNM staging, lymph node metastasis, and reduced survival. Meanwhile, miR-29a was preferentially expressed in normal colon tissues, while B7-H3 transcript levels had no marked differences between tumor and normal tissue specimens. In vitro, miR-29a upregulation resulted in reduced B7-H3 expression. Furthermore, miR-29a upregulation reduced the invasive and migratory abilities of colon carcinoma cells. In animal models, upregulation of miR-29a slowed down the growth of subcutaneous xenotransplanted tumors and resulted in prolonged survival time. MiR-29a downregulates B7-H3 expression and accordingly inhibits colon cancer progression, invasion, and migration, indicating miR-29a and B7-H3 might represent novel molecular targets for advanced immunotherapy in colon cancer.

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Acknowledgements

We had submitted our article to a pre-print server which can be accessed at https://www.researchsquare.com/article/rs-68497/v1. This study was supported by grants from the National Science Foundation of China (NSFC, No. 31770985, No. 82073180), Jiangsu Provincial Key Research and Development Program, China (No. BE2019665), Jiangsu Provincial Medical Youth Talent, China (No. QNRC2016732), Jiangsu Provincial “ Six Peaks Talent ” Program, China (No. 2016-WSW-043), Suzhou Municipal Project of Gusu Health Talent, Young Top Talent, China (No. 2018-057), Gusu Health Talents Cultivation Program, China (No. GSWS2019028), Scientific Research Program of Jiangsu Provincial “333 Talents Projects”, China (No. BRA2019327), and Science and Technology Program of Suzhou City, China (No. SYS2019053, No. SLC201906).

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  1. Jin Wang, Xiaojuan Chen and Chen Xie contributed equally to this work

Authors and Affiliations

  1. Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China

    Jin Wang, Mingbing Sun, Chenrui Hu, Zhe Zhang, Lipeng Luan, Jin Zhou, Jian Zhou, Xinguo Zhu, Xiaoqiang Dong, Dechun Li & Xin Zhao

  2. Department of General Surgery, Suzhou Dushu Lake Hospital (Dushu Lake Hospital Affiliated to Soochow University), Suzhou, China

    Jin Wang

  3. Jiangsu Institute of Clinical Immunology, Soochow University, Suzhou, China

    Jin Wang & Xin Zhao

  4. Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China

    Jin Wang & Xin Zhao

  5. Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Jin Wang & Xin Zhao

  6. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Xiaojuan Chen & Chen Xie

  7. Department of Urology Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China

    Jun Ouyang & Jianglei Zhang

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  1. Jin Wang
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Contributions

XZ and JZ proposed the research project and are the guarantors. JW drafted the manuscript. JW, XC, and CX had equal contributions to the current work. All authors were involved in study design and data interpretation and have reviewed the final version of the manuscript.

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Correspondence to Jianglei Zhang or Xin Zhao.

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The authors declare no conflict of interest concerning the content of the present article.

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Written informed consent was obtained from all patients and the present study had approval from the Ethics Committee of First Affiliated Hospital of Soochow University. All experiments were performed in accordance with relevant guidelines and regulations. The animal studies were carried out at Laboratory Animal Center of Soochow University and performed according to a protocol approved by the animal care and use committee of Soochow University.

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Wang, J., Chen, X., Xie, C. et al. MicroRNA miR-29a Inhibits Colon Cancer Progression by Downregulating B7-H3 Expression: Potential Molecular Targets for Colon Cancer Therapy. Mol Biotechnol 63, 849–861 (2021). https://doi.org/10.1007/s12033-021-00348-1

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