Issue No. 10, October 2017
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, M.Ph., Ph.D., the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by the VIMM members.     
Regulation of microRNA by mda-7/IL-24

  • MicroRNAs (miRNAs or miRs) are small 19-22 nucleotide long, noncoding, single-stranded, and multi-functional RNAs that regulate a diverse assortment of gene and protein functions that impact on a vast network of physiologically relevant pathways.

  • miRNAs interfere with translation or posttranscriptional regulation of their target gene and regulate multiple biological actions exerted by these target genes. In cancer, they function both as oncogenes and tumor suppressor genes displaying differential activity in various cellular contexts.

  • Melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24), is a cytokine that potently induces anti-cancer activity in vitro and in vivo in preclinical animal models, and in a Phase I/II clinical trial in patients with advanced cancers.
 
  • A recent study by Pradhan et al. has uncovered a novel and unique role of mda-7/IL -24 in regulating miRNAs. mda-7/IL-24 downregulates miR-221, a key microRNA in many cancers.
mda-7/IL-24  Mediates Cancer Cell–Specific Death via Regulation of the miR-221-Beclin-1  Axis

mda-7 /IL-24, a member of the IL-10 cytokine gene family, was cloned from terminally differentiating human melanoma cells using subtraction hybridization. mda-7 /IL-24 has established anti-cancer activity in vitro and in vivo in preclinical animal models. Intratumoral injection of an adenovirus expressing mda-7/IL-24 (Ad. mda-7 ; INGN 241), in a phase I/II clinical trial of advanced cancers, demonstrated its therapeutic efficacy . A recent study by Pradhan et al. has uncovered a novel and unique role of mda-7/ IL-24 in the regulation of miRNAs. Several differentially regulated miRNAs, including miR-200c, let7c, and miR-320, were identified by overexpression of mda-7 /IL-24 in an aggressive triple negative breast cancer cell line, MDA-MB-231. miR-200c, an important regulator of tumor metastasis and epithelial-mesenchymal transition, was downregulated by mda-7/ IL-24. miR-17, which regulates the G1-S transition of the cell cycle, and the tumor suppressor miR-185, are upregulated in the mda-7/ IL-24 overexpressing cells. miR-221 is a key microRNA involved in many cancers which plays a critical role in cancer progression by regulating p27, a key modulator of cell cycle and PUMA, a pro-apoptotic gene. Pradhan et al. demonstrated that mda-7/IL-24 downregulates miR-221, which in turn upregulates beclin-1 and promotes toxic autophagy that progresses to apoptosis in breast cancer cells. Furthermore, overexpression of miR-221 rescues cells from mda-7/IL-24 –mediated cell death both in vitro and in vivo in a human breast cancer xenograft model. This study supports a direct role for mda-7/IL-24 in miR-221 regulation in cancer cells, and establishes a novel role for the mda-7/IL-24 -miR-221-beclin-1 axis in cancer cell-specific death.

A njan K. Pradhan, a postdoctoral research scientist in Dr. Paul Fisher’s laboratory at VCU, is the lead author of this paper, and performed much of the biological and animal work. The study was published in Cancer Research in February 2017*. The study was supported by NIH-NCI SPORE P50 CA058236, and by the National Foundation for Cancer Research (NFCR). Microscopy was performed at the VCU - Department of Anatomy & Neurobiology Microscopy Facility, which is supported by funding from NIH/NINDS Center Core Grant 5 P30 NS047463, and NIH-NCI Cancer Center Support Grant P30 CA016059. The VCU Massey Cancer Center Flow Cytometry Shared Resource, supported by funding from NIH-NCI Cancer Center Support Grant P30 CA016059, generated services and products for the research project.
Figure Legend: Schematic representation of mda-7/IL-24 regulating miR-221: mda-7/IL-24 regulates miR-221, which in turn upregulates several downstream genes to block cellular proliferation, and induce apoptotic signals and toxic autophagy. mda-7/IL-24 also regulates several pathways involved in cancer, as shown. Adapted from Pradhan AK et al., Cancer Res. 2017*.

  Publication:
*Pradhan AK, Talukdar S, Bhoopathi P, Shen XN, Emdad L, Das SK, Sarkar D, Fisher PB (2017) mda-7/IL-24 Mediates Cancer Cell-Specific Death via Regulation of miR-221 and the Beclin-1 Axis. Cancer Res. 2017 Feb 15;77(4):949-959. PMCID: PMC5313338 [Available on 2018-02-15] DOI: 10.1158/0008-5472.CAN-16-1731
About the Investigators

Paul B. Fisher, MPh, PhD, is Professor and Chair of Human and Molecular Genetics (HMG), Director of the VCU Institute of Molecular Medicine (VIMM) and Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Anjan K. Pradhan, PhD, Sarmistha Talukdar, PhD and Praveen Bhoopathi, PhD are postdoctoral research scientists in HMG. Swadesh K. Das, PhD and Luni Emdad, MBBS, PhD are both Assistant Professors in HMG and Members of the VIMM. Devanand Sarkar is an Associate Professor in HMG, Associate Scientific Director of Therapeutics in the VIMM, and a Harrison Foundation Distinguished Professor in Cancer Research in the VCU MCC.