CDK11p110 plays a critical role in the tumorigenicity of esophageal squamous cell carcinoma cells and is a potential drug target

Yue Du; Dan Yan; Yongliang Yuan; Jian Xu; Suhua Wang; Zhiheng Yang; Weiyan Cheng; Xin Tian; Quancheng Kan

doi:10.1080/15384101.2019.1577665

CDK11^p110 plays a critical role in the tumorigenicity of esophageal squamous cell carcinoma cells and is a potential drug target

Cell Cycle. 2019 Feb;18(4):452-466. doi: 10.1080/15384101.2019.1577665. Epub 2019 Feb 12.

Authors

Yue Du^{1

2}, Dan Yan^{1

2}, Yongliang Yuan^{1

2}, Jian Xu³, Suhua Wang^{1

2}, Zhiheng Yang^{1

2}, Weiyan Cheng^{1

2}, Xin Tian^{1

2}, Quancheng Kan^{1

2}

Affiliations

¹ a Department of Pharmacy , the First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China.
² b Henan Key Laboratory of Precision Clinical Pharmacy , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China.
³ c Institute of Medicinal Biotechnology , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China.

Abstract

Esophageal squamous cell carcinoma (ESCC) is a serious malignancy with limited options for targeted therapy. The exploration of novel targeted therapies for combating ESCC is urgently needed. Cyclin-dependent kinases (CDKs) play important roles in the progression of cancers; however, the function of CDK11^p110 (cyclin-dependent kinase 11^p110) in ESCC is still unknown. Here, we investigated the effects and molecular mechanisms of CDK11^p110 in the proliferation and growth of ESCC by examining the expression of CDK11^p110 in ESCC tissues and by detecting phenotypic changes in ESCC cells after CDK11^p110 knockdown or overexpression in vitro and in vivo. According to the tissue microarray analysis, compared with its expression level in normal tissues, the expression level of CDK11^p110 was significantly elevated in ESCC tissues; this result was in concordance with the data in TCGA (The Cancer Genome Atlas) datasets. In addition, RNAi-mediated CDK11^p110 silencing exerted a substantial inhibitory effect on the proliferation, clonogenicity and migration ability of ESCC cells. Further study indicated that CDK11^p110 knockdown arrested ESCC cells in the G2/M phase of the cell cycle and induced cell apoptosis. Moreover, stable shRNA-mediated CDK11^p110 knockdown inhibited tumor growth in an ESCC xenograft model, and overexpression of CDK11^p110 enhanced tumor growth. In addition, the Ki67 proliferation index was closely associated with the elevation or depletion of CDK11^p110 in vivo. In summary, this study provides evidence that CDK11^p110 play a critical role in the tumorigenicity of ESCC cells, which suggests that CDK11^p110 may be a promising therapeutic target in ESCC. Abbreviations: CDKs: cyclin-dependent kinases; CDK11: Cyclin-dependent kinase 11; CDK11^p110: Cyclin-dependent kinase 11^p110, the larger isomer of cyclin-dependent kinase 11; ESCC: esophageal squamous cell carcinoma; FACS: fluorescence-activated cell sorting; FDA: the Food and Drug Administration; TCGA: The Cancer Genome Atlas; TMA: tissue microarray.

Keywords: CDK11; ESCC; kinase; target; tumorigenicity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Cell Cycle Checkpoints / genetics
Cell Line, Tumor
Cell Movement / genetics*
Cell Proliferation / genetics*
Cyclin-Dependent Kinases / genetics*
Cyclin-Dependent Kinases / metabolism*
Drug Delivery Systems
Esophageal Neoplasms / metabolism*
Esophageal Neoplasms / pathology
Esophageal Squamous Cell Carcinoma / metabolism*
Esophageal Squamous Cell Carcinoma / pathology
Female
Gene Knockdown Techniques
Heterografts
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
RNA, Small Interfering
Transfection
Tumor Burden / genetics

Substances

RNA, Small Interfering
Cyclin-Dependent Kinases
Cyclin-dependent kinase 11p110, human

Grants and funding

This work was supported by grants from the Major Science and Technology Project of Henan Province (No. 161100310100) and the National Natural Science Foundation of China (No. 31670895, U1504831, and 81703417).