Dysregulation of adenosine kinase isoforms in breast cancer
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Bahar Shamloo1,*, Nandita Kumar1, Randall H. Owen1, Jesica Reemmer1, John Ost2, R. Serene Perkins2,3 and Hai-Ying Shen1
1 Department of Translational Neuroscience, Legacy Research Institute, Legacy Health, Portland, OR 97232, USA
2 Legacy Tumor Bank, Legacy Research Institute, Legacy Health, Portland, OR 97232, USA
3 Mid-Columbia Medical Center, The Dalles, OR 97058, USA
* Current communication address:
|Hai-Ying Shen,||email:||[email protected]|
|Bahar Shamloo,||email:||[email protected]|
Keywords: adenosine kinase; breast cancer; adenosine kinase isoforms; metastasis; proliferation
Received: August 05, 2019 Accepted: November 07, 2019 Published: December 31, 2019
Dysregulated adenosine signaling pathway has been evidenced in the pathogenesis of breast cancer. However, the role of adenosine kinase (ADK) in tumorigenesis remains unclear while it crucially regulates the removal and availability of adenosine. ADK has two isoforms that localize to discrete subcellular spaces: i.e., nuclear, long-isoform (ADK-L) and cytosolic, short-isoform (ADK-S). We hypothesized that these two ADK isoforms would be differentially expressed in breast cancer and may contribute to divergent cellular actions in cancer. In this study, we examined the expression profiles of ADK isoforms in breast cancer tissues from 46 patient and followed up with an in vitro investigation by knocking down the expression of ADK-L or ADK-S using CRISPR gene editing to evaluate the role of ADK isoform in cancer progression and metastasis of cultured triple-negative breast cancer cell line MDA-MB-231. We demonstrated that (i) ADK-L expression level was significantly increased in breast cancer tissues versus paired normal tissues adjacent to tumor, whereas the ADK-S expression levels were not significantly different between cancerous and normal tissues; (ii) CRISPR/Cas9-mediated downregulation of ADK isoforms, led to suppressed cellular proliferation, division, and migration of cultured breast cancer cells; (iii) ADK-L knockdown significantly upregulated gene expression of matrix metalloproteinase (ADAM23, 9.93-fold; MMP9, 24.58-fold) and downregulated expression of cyclin D2 (CCND2, -30.76-fold), adhesive glycoprotein THBS1 (-8.28-fold), and cystatin E/M (CST6, -16.32-fold). Our findings suggest a potential role of ADK-L in mitogenesis, tumorigenesis, and tumor-associated tissue remodeling and invasion; and the manipulation of ADK-L holds promise as a therapeutic strategy for aggressive breast cancer.
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