Downregulation of APRIN expression increases cancer cell proliferation via an interleukin-6/STAT3/cyclin&nbsp;D axis

Sohn,Min-Shik; Kang,Miae; Kang,Seong-Man; Bae,Sangwoo

doi:10.3892/ol.2020.12317

Downregulation of APRIN expression increases cancer cell proliferation via an interleukin-6/STAT3/cyclin D axis

Authors:
- Min-Shik Sohn
- Miae Kang
- Seong-Man Kang
- Sangwoo Bae
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Affiliations: Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences (KIRAMS), Nowon-Gu, Seoul 139-706, Republic of Korea, Graduate School of Life Sciences, Korea University, Inchonro, Seongbuk-Gu, Seoul 139-706, Republic of Korea
Published online on: November 18, 2020 https://doi.org/10.3892/ol.2020.12317
Article Number: 55
Copyright: © Sohn et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

APRIN is a putative tumor suppressor whose expression is low in a variety of cancer cells. While decreased expression of APRIN leads to increased cell proliferation, unfavorable diagnosis or metastases in various cancer types, there is limited knowledge on the cellular mechanism of APRIN in cellular responses. The effect of APRIN depletion on cancer cell proliferation was examined in the present study, and the IL‑6/STAT3/cyclin D axis was identified as a novel regulatory mechanism. Stable depletion of APRIN in cancer cells resulted in increased cell proliferation. Cytokine array analysis of the cells revealed that downregulation of APRIN induced secretion of interleukin‑6 (IL‑6) with corresponding activation of STAT3, a downstream intracellular mediator. Levels of cyclin D1 were increased in cells with APRIN depletion and cyclin D1 expression was associated with increased STAT3 binding on cyclin D1 promoter sequence; assessed by chromatin immunoprecipitation assay. The addition of an IL‑6 neutralizing antibody P620 to the cell culture attenuated STAT3 activation and cyclin D1 expression in APRIN‑depleted cells with corresponding decrease in cell proliferation. These experiments suggest that APRIN regulates cancer cell proliferation via an IL‑6/STAT3/cyclin D axis and that targeting this axis in APRIN‑associated cancer might provide a novel therapeutic approach.

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