Oncotarget

Research Papers:

IL-24 modulates the high mobility group (HMG) A1/miR222 /AKT signaling in lung cancer cells

Janani Panneerselvam _, Akhil Srivastava, Ranganayaki Muralidharan, Qi Wang, Wei Zheng, Lichao Zhao, Alshine Chen, Yan D. Zhao, Anupama Munshi and Rajagopal Ramesh

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Oncotarget. 2016; 7:70247-70263. https://doi.org/10.18632/oncotarget.11838

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Abstract

Janani Panneerselvam1,4, Akhil Srivastava1,4, Ranganayaki Muralidharan1,4, Qi Wang1,4, Wei Zheng1, Lichao Zhao1,4, Alshine Chen3,4, Yan D. Zhao3,4, Anupama Munshi2,4, Rajagopal Ramesh1,4,5

1Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA

2Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA

3Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA

4Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA

5Graduate Program in Biomedical Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA

Correspondence to:

Rajagopal Ramesh, email: rajagopal-ramesh@ouhsc.edu

Keywords: IL-24, lung cancer, HMGA1, miR222-3p, metastasis

Received: April 21, 2016    Accepted: August 24, 2016    Published: September 02, 2016

ABSTRACT

Interleukin (IL)-24, a novel tumor suppressor/cytokine exhibits antitumor activity against a broad-spectrum of human cancer cells. In a recent study, we showed that IL-24 inhibited AKT in lung cancer cells. However, the molecular mechanism of AKT inhibition by IL-24 remains elusive.

The high mobility group (HMG) A1 a member of the non-histone chromosomal proteins and commonly referred to as architectural transcription factor, regulates transcription of various genes involved in cell growth and survival. Overexpression of HMGA1 has been shown to be associated with tumor progression and metastasis in several cancers, including human lung cancer. A recent study demonstrated that HMGA1 activates AKT function by reducing the activity of the protein phosphatase, phosphatase 2A subunit B (PPP2R2A) via the oncogenic micro (mi) RNA-222. Based on this report we hypothesized that IL-24-mediated AKT inhibition involved the HMGA1/miR-222 axis.

To test our hypothesis, in the present study we used a H1299 lung cancer cell line that expressed exogenous human IL-24 when induced with doxycycline (DOX). Induction of IL-24 expression in the tumor cells markedly reduced HMGA1 mRNA and protein levels. Using a mechanistic approach, we found that IL-24 reduced miR-222-3p and -5p levels, as determined by qRT-PCR. Associated with HMGA1 and miR-222 inhibition was a marked increase in PPP2R2A, with a concomitant decrease in phosphorylated AKTT308/S473 expression. SiRNA-mediated knockdown of HMGA1 in combination with IL-24 significantly reduced AKT T308/S473 protein expression and greatly reduced cell migration and invasion compared with individual treatments. Further combination of IL-24 and a miR-222-3p inhibitor significantly increased PPP2R2A expression.

Our results demonstrate for the first time that IL-24 inhibits AKT via regulating the HMGA1/miR-222 signaling node in human lung cancer cells and acts as an effective tumor suppressor. Thus, a therapy combining IL-24 with HMGA1 siRNA or miR-222-3p inhibitor should present effective treatment of lung cancer.


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