Gene Summary

Gene:IL24; interleukin 24
Aliases: C49A, FISP, MDA7, MOB5, ST16, IL10B
Summary:This gene encodes a member of the IL10 family of cytokines. It was identified as a gene induced during terminal differentiation in melanoma cells. The protein encoded by this gene can induce apoptosis selectively in various cancer cells. Overexpression of this gene leads to elevated expression of several GADD family genes, which correlates with the induction of apoptosis. The phosphorylation of mitogen-activated protein kinase 14 (MAPK7/P38), and heat shock 27kDa protein 1 (HSPB2/HSP27) are found to be induced by this gene in melanoma cells, but not in normal immortal melanocytes. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
IL24 is implicated in:
- apoptotic process
- cytokine activity
- extracellular space
Data from Gene Ontology via CGAP
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IL24 (cancer-related)

Maehana S, Matsumoto Y, Kojima F, Kitasato H
Interleukin-24 Transduction Modulates Human Prostate Cancer Malignancy Mediated by Regulation of Anchorage Dependence.
Anticancer Res. 2019; 39(7):3719-3725 [PubMed] Related Publications
BACKGROUND: Hormone therapy and chemotherapy are not effective for castrate-resistant prostate cancer, thus development of novel treatment strategies is required. Gene therapy involving transient high-copy transfection of interleukin (IL)-24 with an adenoviral vector can exert antitumor activity; however, the effects of stable IL-24 transfection are not fully understood. The aim of this study was to investigate the effects of IL-24 overexpression in prostate cancer cells, in vitro.
MATERIALS AND METHODS: DU145 cells were transfected the IL-24 gene using a retroviral vector. Apoptosis induction was investigated by the cell death detection ELISA, and the gene expression was analyzed by real time RT-PCR.
RESULTS: IL-24 transduction suppressed the growth of prostate cancer and induced tumor cell apoptosis. In addition, up-regulation of epithelial markers and down-regulation of mesenchymal markers were noted, suggesting that tumor aggressiveness was reduced.
CONCLUSION: Introduction of IL-24 displays antitumor activity both by induction of apoptosis and regulation of anchorage dependence.

Luo H, Chen Y, Niu L, et al.
Hepatoma Cell-Targeted Cationized Silk Fibroin as a Carrier for the Inhibitor of Growth 4-Interleukin-24 Double Gene Plasmid.
J Biomed Nanotechnol. 2019; 15(7):1622-1635 [PubMed] Related Publications
The construction of a targeted gene delivery system with low cytotoxicity to normal tissues is an urgent need for the clinical treatment of liver cancer. In this study,

Liu L, Ma J, Qin L, et al.
Interleukin-24 enhancing antitumor activity of chimeric oncolytic adenovirus for treating acute promyelocytic leukemia cell.
Medicine (Baltimore). 2019; 98(22):e15875 [PubMed] Related Publications
BACKGROUND: Acute promyelocytic leukaemia (APL) is a clonal disease arising by hematopoietic stem cell (HSC), which characterized by inappropriate proliferation/differentiation or survival of immature myeloid progenitors. Oncolytic adenoviruses have been under widespread investigation as anticancer agents. Recently, our data suggested that tumor cells were cured by AdCN205-IL-24, an adenovirus serotype 5-based conditionally replicating adenovirus expressing IL-24 after infection.
METHODS: In this study, we created a novel fiber chimeric oncolytic adenovirus AdCN306-IL-24 that has Ad11 tropism and approved CAR (coxsackie adenovirus receptor, CAR)-independent cell entry, which could allow development of selective cytopathic effects (CPE) in APL cells in vitro.
RESULTS: Formidable cytotoxic effect was specifically implemented in APL cells after infection with AdCN306-IL-24. The expression of IL-24 was up-regulated upon treated with accepted tumors. And the vector also induced superior cytolytic effects activity in APL cells by activation of programmed cell death.
CONCLUSIONS: Taken together, our data suggested that chimeric oncolytic adenovirus AdCN306-IL-24 could express IL-24 gene, representing a potential therapeutics for acute promyelocytic leukemia.

Pradhan AK, Bhoopathi P, Talukdar S, et al.
MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF.
Proc Natl Acad Sci U S A. 2019; 116(12):5687-5692 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Melanoma differentiation-associated gene-7/interleukin-24 (

Rasoolian M, Kheirollahi M, Hosseini SY
MDA-7/interleukin 24 (IL-24) in tumor gene therapy: application of tumor penetrating/homing peptides for improvement of the effects.
Expert Opin Biol Ther. 2019; 19(3):211-223 [PubMed] Related Publications
INTRODUCTION: MDA-7/Interleukin-24 (IL-24), as a pleiotropic cytokine, exhibits a specific tumor suppression property that has attracted a great deal of attention. While its anti-tumor induction is mostly attributed to endogenous gene expression, attachment of secreted MDA-7/IL-24 to cognate receptors also triggers the death of cancerous cell via different pathways. Therefore, precise targeting of secreted MDA-7/IL-24 to tumor cells would render it more efficacy and specificity.
AREAS COVERED: In order to target soluble cytokines, particularly MDA-7/IL-24 to the neighbor tumor sites and enhance their therapeutic efficiency, fusing with cell penetrating peptides (CPPs) or Tumor homing peptides (THPs) seems logical due to the improvement of their bystander effects. Although the detailed anti-tumor mechanisms of endogenous mda-7/IL-24 have been largely investigated, the significance of the secreted form in these activities and methods of its improving by CPPs or THPs need more discussion.
EXPERT OPINION: While the employment of CPPs/THPs for the improvement of cytokine gene therapy is desirable, to create fusions of CPPs/THPs with MDA-7/IL-24, some hurdles are not avoidable. Regarding our expertise, herein, the importance of CPPs/THPs, needs for their elegant designing in a fusion structure, and their applications in cytokine gene therapy are discussed with a special focus on mda-7/IL-24.

Persaud L, Mighty J, Zhong X, et al.
IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells.
Int J Mol Sci. 2018; 19(11) [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2α phosphorylation and activating transcription factor 4 (ATF4) action. Our studies show for the first time that cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation is required for IL-24-induced cell death in a variety of breast cancer cell lines and this event increases ATF4 activity. We demonstrate an undocumented role for PKA in regulating IL-24-induced cell death, whereby PKA stimulates phosphorylation of p38 mitogen-activated protein kinase and upregulates extrinsic apoptotic factors of the Fas/FasL signaling pathway and death receptor 4 expression. We also demonstrate that phosphorylation and nuclear import of tumor suppressor TP53 occurs downstream of IL-24-mediated PKA activation. These discoveries provide the first mechanistic insights into the function of PKA as a key regulator of the extrinsic pathway, ER stress, and TP53 activation triggered by IL-24.

Wang L, Zhao H, Xu Y, et al.
Systematic identification of lincRNA-based prognostic biomarkers by integrating lincRNA expression and copy number variation in lung adenocarcinoma.
Int J Cancer. 2019; 144(7):1723-1734 [PubMed] Related Publications
Copy number alterations (CNAs) of lincRNAs act as one of important mechanisms in disrupting lincRNA expression which may play critical roles during tumorigenesis in lung adenocarcinoma (LUAD). The copy number alterations of lincRNAs can mark the spectrum of cancer progression and may serve as biomarkers for prognosis in LUAD, however it is rarely studied. We analyzed RNASeq data for 488 LUAD patients from TCGA portal and 58 healthy subjects to identify prognostic lincRNAs predictive of patient survival. Computational analysis entailing integration of expression and copy number alteration data revealed five prognostic lincRNAs: RBPMS-AS1, TDRKH-AS1, LINC00578, RP11-470 M17.2 and LINC00941. The copy number alterations in the LINC00578 and RP11-470 M17.2 genes were positively associated with the longer overall survival of LUAD patients. The CNA in LINC00941 was negatively associated with the longer overall survival. Copy number amplification significantly correlated with increased expression of TDRKH-AS1, which regulates telomere organization and EZH2-mediated epigenetic silencing of CDKN1A, CDKN1B and IL24. Decreased survival of LUAD patients was associated with high LINC00941 expression. The LINC00941 regulates the PI3K-AKT signaling pathway, focal adhesion by influencing potential targets, such as KRAS proto-oncogene GTPase and VEGFC. These lincRNA-based prognostic biomarkers may destroy important cancer-related biological processes contributing to LUAD prognosis. In summary, we demonstrate the prognostic potential of four differentially expressed lincRNAs with copy number alterations (RBPMS-AS1, TDRKH-AS1, LINC00578 and RP11-470 M17.2) that are positively associated with longer overall survival of LUAD patients. One differentially expressed lincRNA LINC00941 with copy number alterations was negatively associated with longer overall survival of LUAD patients.

Kim JY, Kim JC, Lee JY, Park MJ
Oct4 suppresses IR‑induced premature senescence in breast cancer cells through STAT3- and NF‑κB-mediated IL‑24 production.
Int J Oncol. 2018; 53(1):47-58 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Breast cancer stem cells (BCSCs) are a small subpopulation of breast cancer cells that have been proposed to be a primary cause of failure of therapies, including ionizing radiation (IR). Their embryonic stem-like signature is associated with poor clinical outcome. In the present study, the function of octamer-binding transcription factor 4 (Oct4), an embryonic stem cell factor, in the resistance of BCSCs to IR was investigated. Mammosphere cells exhibited increased expression of stemness-associated genes, including Oct4 and sex‑determining region Y‑box 2 (Sox2), and were more resistant to IR compared with serum-cultured monolayer cells. IR‑resistant MCF7 cells also exhibited significantly increased expression of Oct4. To investigate the possible involvement of Oct4 in IR resistance of breast cancer cells, cells were transfected with Oct4. Ectopic expression of Oct4 increased the clonogenic survival of MCF7 cells following IR, which was reversed by treatment with small interfering RNA (siRNA) targeting Oct4. Oct4 expression decreased phosphorylated histone H2AX (γ-H2AX) focus formation and suppressed IR‑induced premature senescence in these cells. Mammosphere, IR‑resistant and Oct4‑overexpressing MCF7 cells exhibited enhanced phosphorylation of signal transducer and activation of transcription 3 (STAT3) (Tyr705) and inhibitor of nuclear factor κB (NF‑κB), and blockade of these pathways with siRNA against STAT3 and/or specific inhibitors of STAT3 and NF‑κB significantly increased IR‑induced senescence. Secretome analysis revealed that Oct4 upregulated interleukin 24 (IL‑24) expression through STAT3 and NF‑κB signaling, and siRNA against IL‑24 increased IR‑induced senescence, whereas recombinant human IL‑24 suppressed it. The results of the present study indicated that Oct4 confers IR resistance on breast cancer cells by suppressing IR‑induced premature senescence through STAT3- and NF‑κB-mediated IL‑24 production.

Ma C, Zhao LL, Zhao HJ, et al.
Lentivirus‑mediated MDA7/IL24 expression inhibits the proliferation of hepatocellular carcinoma cells.
Mol Med Rep. 2018; 17(4):5764-5773 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
MDA7/IL24 is a member of the IL‑10 gene family that functions as a cytokine. Notably, supra‑physiological endogenous MDA7 levels have been indicated to suppress tumor growth and induce apoptosis in different cancer types. In the present study, MDA7 roles were investigated during the proliferation of hepatocellular carcinoma (HCC) cells and the molecular mechanisms underlying this process. A lentiviral vector expressing MDA7/IL24 (LV‑MDA7/IL24) was constructed and used to infect HCC SMMC‑7721 cells. The expression levels of MDA7/IL24 in these cells were determined using RT‑qPCR and western blot analysis. The effects of LV‑MDA7/IL24 on cell proliferation were analyzed using MTT and colony formation assays. Furthermore, the influence of LV‑MDA7/IL24 on cell apoptosis and cell cycle distribution were detected using flow cytometry. The underlying molecular mechanisms were investigated using microarray and western blot analysis. The expression of MDA7/IL24 was confirmed to be significantly increased in the cells infected with LV‑MDA7/IL24 compared with that the negative‑control infected group. Lentivirus‑mediated MDA7/IL24 expression was found to inhibit HCC cell proliferation and colony formation, and it also induced cell arrest and apoptosis. Microarray analysis and western blotting results indicated that multiple cancer‑associated pathways and oncogenes are regulated by MDA7/IL24, including cell cycle regulatory and apoptosis activation pathway. In conclusion, it was determined that MDA7/IL24 inhibits the proliferation and reduces the tumorigenicity of HCC cells by regulating cell cycle progression and inducing apoptosis, indicating that it may be used as a potential prognostic and therapeutic target in HCC.

Yu X, Miao J, Xia W, Gu ZJ
Immunogenicity moderation effect of interleukin-24 on myelogenous leukemia cells.
Anticancer Drugs. 2018; 29(4):353-363 [PubMed] Related Publications
Previous studies have shown that interleukin-24 (IL-24) has tumor-suppressing activity by multiple pathways. However, the immunogenicity moderation effect of IL-24 on malignant cells has not been explored extensively. In this study, we investigated the role of IL-24 in immunogenicity modulation of the myelogenous leukemia cells. Data show that myelogenous leukemia cells express low levels of immunogenicity molecules. Treatment with IL-24 could enhance leukemia cell immunogenicity, predominantly regulate leukemia cells to produce immune-associated cytokines, and improve the cytotoxic sensitivity of these cells to immune effector cells. IL-24 expression could retard transplanted leukemia cell tumor growth in vivo in athymic nude mice. Moreover, IL-24 had marked effects on downregulating the expression of angiogenesis-related proteins vascular endothelial growth factor, cluster of differentiation (CD) 31, CD34, collagen IV and metastasis-related factors CD147, membrane type-1 matrix metalloproteinase (MMP), and MMP-2 and MMP-9 in transplanted tumors. These findings indicated novel functions of this antitumor gene and characterized IL-24 as a promising agent for further clinical trial for hematologic malignancy immunotherapy.

Ma M, Zhao R, Yang X, et al.
Low expression of Mda-7/IL-24 and high expression of C-myb in tumour tissues are predictors of poor prognosis for Burkitt lymphoma patients.
Hematology. 2018; 23(8):448-455 [PubMed] Related Publications
Objectives Burkitt lymphoma is one of the most common types of haematopoietic malignancy in children and adolescents. Mda-7/IL-24 had been identified as a differentiation inducer of Burkitt lymphoma cells. Previous studies have revealed that knockdown of C-myb can also lead to the terminal differentiation of Burkitt lymphoma cells. The aim of the present study was to investigate the correlation between the expression of Mda-7/IL-24 and C-myb, as well as their prognostic significance, for Burkitt lymphoma patients. Methods The tumour tissues were collected from 59 cases of Burkitt lymphoma patients and detected with Western blotting and immunohistochemistry. Results The results showed that the expression of Mda-7/IL-24 was lower, whereas the expression of C-myb was higher in Burkitt lymphoma tissues compared to specimens of normal lymph node tissues. Furthermore, C-myb expression was negatively correlated with Mda-7/IL-24 expression at the protein level in Burkitt lymphoma tissues and cell lines. Both the expression of Mda-7/IL-24 and C-myb in Burkitt lymphoma tissues was associated with some clinicopathological parameters, such as clinical stage, infiltration in the bone marrow, Ki67 and overall survival rates. Conclusion These results indicated that low expression of Mda-7/IL-24 along with high expression of C-myb are predictors for poor prognosis of Burkitt lymphoma patients; this outcome suggests that Mda-7/IL-24 and C-myb might be potential targets for clinical treatment of Burkitt lymphoma.
ABBREVIATIONS: Mda-7/IL-24: melanoma differentiation associated gene7/interleukin 24; FCM: flow cytometry; Ecog: Eastern Cooperative Oncology Group; IPI: International lymphoma prognosis index.

Xu M, Tang X, Guo J, et al.
Reversal effect of adenovirus-mediated human interleukin 24 transfection on the cisplatin resistance of A549/DDP lung cancer cells.
Oncol Rep. 2017; 38(5):2843-2851 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Interleukin-24 (IL-24) is a tumor-suppressor gene that has been documented in human melanoma cells. IL-24 has marked antitumor activities on various types of human cancer, but its underlying mechanism remains unclear. In the present, we investigated the effects of human IL-24 (hIL-24) on the chemotherapy resistance of lung cancer cells. The cisplatin (DDP)-resistant lung carcinoma cell line A549/DDP was subjected to adenovirus-mediated transfection with the human IL-24 gene (Ad-hIL-24). The growth-inhibitory and apoptotic effects of Ad-hIL-24 on A549/DDP cells were observed, and the expression levels of AKT, phosphorylated-AKT (p-AKT) and P-glycoprotein (P-gp) were detected. Ad-hIL-24 significantly decreased the levels of p-AKT and P-gp, and effectively inhibited A549/DDP cell growth. Furthermore, A549/DDP cells exhibited a significantly increased rate of apoptosis, as well as G2/M-phase arrest, following transfection with Ad-hIL-24, and these effects were increased in cells treated with Ad-IL-24 combined with DDP when compared with those treated with Ad-hIL-24 or DDP alone. These results suggest that hIL-24 can reverse the DDP resistance of lung cancer cells, and that the associated mechanism involves the induction of apoptosis and G2/M-phase arrest through the phosphoinositide3-kinase (PI3K)/AKT signaling pathway, as well as a decrease in drug resistance through P-gp expression.

Zhu Q, Pan X, Sun Y, et al.
Biological nanoparticles carrying the Hmda-7 gene are effective in inhibiting pancreatic cancer in vitro and in vivo.
PLoS One. 2017; 12(10):e0185507 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
OBJECTIVES: Pancreatic cancer is one of the most common malignancies of the digestive system, and remains a clinical challenge. This study aimed to assess the effects of bovine serum albumin (BSA) nanoparticles carrying the hMDA-7 gene (BSA-NP-hMDA-7) in the treatment of pancreatic cancer.
METHODS: BSA-NP-hMDA-7 was generated by nanotechnology and gene recombination technology. A total of 5 BXPC-3 or PANC-1 pancreatic cancer cell groups were examined, including Control, BSA-NPs, Empty vector, hMDA-7 plasmid, and hMDA-7 BSA-NPs groups, respectively. Proliferation and apoptosis of cultured cells were assessed by the MTT method and flow-cytometry, respectively. In addition, pancreatic cancer models were established with both cell lines in nude mice, and the expression profiles of hMDA-7 and VEGF in cancer tissues were measured by Western blot and immunohistochemistry.
RESULTS: BSA-NP-hMDA-7 nanoparticles were successfully generated, and significantly inhibited the proliferation of BXPC-3 and PANC-1 cells; in addition, apoptosis rates were higher in both cell lines after treatment with BSA-NP-hMDA-7 (P<0.05). Nude mouse xenograft studies indicated that treatment with BSA-NP-hMDA-7 nanoparticles resulted in decreased tumor size. Moreover, the hMDA-7 protein was found in tumor tissues after hMDA-7 gene transfection, while BSA-NP-hMDA-7 significantly suppressed VEGF expression in tumor tissues. Similar results were obtained for both BXPC-3 and PANC-1 xenograft models.
CONCLUSION: BSA nanoparticles carrying the hMDA-7 gene effectively transfected BXPC-3 and PANC-1 pancreatic cancer cells, causing reduced cell proliferation and enhanced apoptosis in vitro. In mouse xenografts, BSA-NP-hMDA-7 treatment decreased tumor size and reduced VEGF expression. These findings indicated that BSA-NP-hMDA-7 might exert anticancer effects via VEGF suppression.

Zhang L, Wang Y, Li X, et al.
ZBTB7A Enhances Osteosarcoma Chemoresistance by Transcriptionally Repressing lncRNALINC00473-IL24 Activity.
Neoplasia. 2017; 19(11):908-918 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Chemoresistance remains a major drawback to osteosarcoma treatment. ZBTB7A, a member of the POK transcription repressor family, was shown to play an important role in tumorigenesis. However, the effect of ZBTB7A on osteosarcoma chemoresistance is completely unknown. In this study, we found that ZBTB7A is increased in cisplatin-resistant osteosarcoma cells and that elevated ZBTB7A inhibits cisplatin-induced apoptosis by repressing LINC00473 expression. Further mechanistic studies revealed that ZBTB7A directly binds to the promoter and suppresses the transcription of LINC00473. Additionally, our data indicate that LINC00473 interacts with the transcript factor C/EBPβ, facilitating its binding to the promoter of IL24, leading to decrease chemoresistance. Thus, these findings indicate that the ZBTB7A-mediated LINC00473-C/EBPβ-IL24 pathway is a promising novel target for overcoming cisplatin resistance in osteosarcoma.

Xia L, Xiao X, Liu WL, et al.
Coactosin-like protein CLP/Cotl1 suppresses breast cancer growth through activation of IL-24/PERP and inhibition of non-canonical TGFβ signaling.
Oncogene. 2018; 37(3):323-331 [PubMed] Related Publications
Coactosin-like protein (CLP, or Cotl1), is an F-actin-binding protein, whose role in cancer is largely unknown. Here we show that CLP/Cotl1 is highly expressed in a rat epithelial breast cancer cell line (FE1.3) compared with its mesenchymal counterpart (FE1.2). Knockdown of CLP/Cotl1 in FE1.3 cells increased cell proliferation, whereas its overexpression in FE1.2 cells inhibited proliferation in culture and reduced tumor growth in xenograft assays in mice. Mechanistically, we identified two major pathways through which CLP/Cotl1 exerts its suppressive effects. First, CLP/Cotl1 re-expression in FE1.2 and in human MCF7 breast cancer cells induced expression of the growth-suppressor gene interleukin-24 (IL-24), which independently of p53 upregulates the tumor-suppressor genes p53 apoptosis effector related to PMP-22 (PERP) and p21

Ma M, Yang X, Zhao L, et al.
Mda‑7/IL‑24 induces the differentiation of B cell lymphoma via activation of the P38 mitogen activated protein kinase signaling pathway.
Mol Med Rep. 2017; 16(4):5633-5642 [PubMed] Related Publications
Interleukin 24 (IL‑24) is a unique cytokine encoded by the melanoma differentiation associated gene‑7 (Mda‑7), and was first discovered inhuman melanoma cells. Exogenous Mda‑7/IL‑24 has been shown to inhibit the proliferation and invasion of a broad spectrum of human cancer cells, but its effect on the differentiation of B cell lymphoma is not yet clear. To the best of our knowledge, the present study demonstrated for the first time that overexpressing Mda‑7/IL‑24 can induce differentiation in human B cell lymphomacells, and the underlying mechanism was investigated. The proliferation of stable Mda‑7/IL‑24 overexpressing Raji and Daudi cells was assessed by the MTS method. The immunophenotype, apoptosis level and cell cycle distribution of Raji and Daudi cells were analyzed by flow cytometry. The expression of PR domain zinc finger protein 1 (Blimp1) and B‑cell lymphoma 6 (Bcl6) were analyzed by western blotting. Additionally, western blotting assay was also performed to study the effect of Mda‑7/IL‑24 on the activity of the P38 mitogen activated protein kinase (MAPK) signaling pathway in Raji and Daudi cells. Proliferation of Raji and Daudi cells overexpressing Mda‑7/IL‑24 was inhibited significantly, compared with those of parent cells and cells transfected with the empty vector alone. Apoptosis was not involved in the proliferation inhibition, while the cell cycle was arrested in G1 phase in the Raji and Daudi cells overexpressing Mda‑7/IL‑24. Overexpressing Mda‑7/IL‑24 resulted in a significantly decreased expression of cluster of differentiation (CD)10, and increased expression of CD45 and CD138 in the cell surface of Raji and Daudi cells. The expression of Blimp1 was upregulated, while the levels of Bcl6 protein was downregulated, in Raji and Daudi cells overexpressing Mda‑7/IL‑24. Furthermore, the activities of the P38 MAPK signaling pathway in lymphoma cells were upregulated. These results indicated that Mda‑7/IL‑24 could induce terminal differentiation of B lymphoma cells by regulating the expression of Blimp1 and Bcl6 via altering the P38 MAPK signaling pathway, suggesting that Mda‑7/IL‑24 may therefore be a potential differentiation therapeutic agent to be applied in clinical treatment of B cell lymphoma.

Wang L, Vuletic I, Deng D, et al.
Bifidobacterium breve as a delivery vector of IL-24 gene therapy for head and neck squamous cell carcinoma in vivo.
Gene Ther. 2017; 24(11):699-705 [PubMed] Related Publications
Beneficial bacteria are becoming ever more popular gene delivery method for hypoxia-tumor targeting in vivo. In this study we investigated the therapeutic effect of new recombinant Bifidobacterium breve strain expressing interleukin (IL)-24 gene (B. breve-IL24) on head and neck tumor xenograft in mice. Briefly, B. breve transformants were obtained through electro-transformation. Bacteria-tumor-targeting ability were analyzed in vivo over different time points (1, 3 and 7 days post-bacteria injection). Furthermore, the therapeutic effect of bacteria on tumor cells in vivo were analyzed as follows: 30 Balb/c nude mice bearing subcutaneous tumor were randomly divided in three groups (Drug group, green fluorescent protein (GFP) group and Saline group). The therapy lasted for 2 weeks and included B. breve-IL24 administration via tail vein for Drug group, B. breve-GFP for GFP group and phosphate buffered saline for Saline group. The tumor growth was monitored using standard caliper technique, while the apoptosis induction in vivo was analyzed by Real-time Positron Emission Tomography/Computed Tomography (PET/CT) imaging ([18F]-ML-10 tracer). At the end of the experiment, tumor tissues were collected and analyzed by western blotting. Briefly, our results suggested that our new recombinant bacterium has the capability of targeting tumor tissue in vivo. As for the therapeutic effect, our new strain has revealed to be a promising therapeutic approach against tumor growth in vivo. Briefly, higher tumor growth inhibition and higher tumor cell apoptosis induction were observed in Drug group compared with the GFP and Saline groups. To conclude, a new recombinant strain B. breve-IL24 offers a novel, safe and clinically acceptable therapeutic approach for tumor therapy in vivo.

Bina S, Hosseini SY, Shenavar F, et al.
The Effect of RGD/NGR Peptide Modification of Melanoma Differentiation-Associated Gene-7/Interleukin-24 on Its Receptor Attachment, an In Silico Analysis.
Cancer Biother Radiopharm. 2017; 32(6):205-214 [PubMed] Related Publications
Melanoma differentiation-associated gene-7 (mda-7/interleukin [IL]-24), a unique tumor suppressor gene, induces selective apoptosis in tumor cells. Secreted IL-24 binds to heterodimeric receptor complexes of IL-20R1/IL-20R2, IL-22R1/IL-20R2, or sigma-1 receptor (Sig1R) that consequently enhances apoptosis. However, this mechanism is not well understood and most likely involves different pathways. Targeting of cytokine by tumor homing peptides (THPs) to the tumor cell surface molecule-like integrin shows to be beneficial in gene immunotherapy approaches. In this study, the in silico targeting of RGD/NGR-modified IL-24 to tumor cells was conducted. In this regard, the sequences of six new synthetic IL-24s that have been modified by RGD (Arg-Gly-Asp) or NGR (CRNGRGPDC) were aligned and their structures were modeled through homology modeling to evaluate their attachment potential to cognate receptor complexes such as IL-20R1/IL-20R2, IL-22R1/IL-20R2, or Sig1R. The results of homology modeling showed that modification of IL-24 with RGD motif in N-terminal and middle of this protein exhibited stronger interaction with cognate receptors. These results also demonstrated that modified IL-24 with RGD motif in the C-terminal has lost native activity. However, the interaction of THP-modified IL-24 with Sig1R would not be affected to that extent, interestingly. Conclusively, in silico analysis showed that modification of IL-24 with THPs needs a more detailed study as these modifications may disrupt native interaction with receptors and reduce apoptosis induction property. This structural analysis gives us a better understanding of mda-7/IL-24 interaction with cognate receptors and helps a more rational design for further cytokine modification.

Sree Latha T, Reddy MC, Muthukonda SV, et al.
In vitro and in vivo evaluation of anti-cancer activity: Shape-dependent properties of TiO
Mater Sci Eng C Mater Biol Appl. 2017; 78:969-977 [PubMed] Related Publications
Cancer is a complex and widespread disease, and it is going to be the first cause of death in the world. Chemotherapy has been used to treat cancer, but it is detrimental to immune cells and known to induce numerous side effects. Therefore it is imperative to develop new drugs for the treatment of cancer without any side effects and toxicity. TiO

Persaud L, Zhong X, Alvarado G, et al.
eIF2α Phosphorylation Mediates IL24-Induced Apoptosis through Inhibition of Translation.
Mol Cancer Res. 2017; 15(8):1117-1124 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
IL24 is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor-suppressor activities of IL24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. Supra-physiologic activation and/or overexpression of translation initiation factors are implicated in the initiation and progression of cancer animal models as well as a subset of human cancers. Activation and/or overexpression of translation initiation factors correlate with aggressiveness of cancer and poor prognosis. Two rate-limiting translation initiation complexes, the ternary complex and the eIF4F complex, are regulated by eIF2α and 4E-BP1 phosphorylation, respectively. The work reported here provides direct evidence that IL24 induces inhibition of translation initiation leading to apoptosis in squamous cell carcinoma. A dominant constitutively active mutant of eIF2α, which is resistant to phosphorylation, was used to determine the involvement of eIF2α in IL24-induced apoptosis. Treatment with IL24 resulted in inhibition of protein synthesis, expression of downstream biomarkers of ternary complex depletion such as CHOP, and induction of apoptosis in cancer cells. The constitutively active nonphosphorylatable mutant of eIF2α, eIF2α-S51A, reversed both the IL24-mediated translational block and IL24-induced apoptosis. Intriguingly, IL24 treatment also caused hypophosphorylation of 4E-BP1, which binds to eIF4E with high affinity, thus preventing its association with eIF4G and therefore preventing elF4F complex assembly.

Liu B, Chen F, Wu Y, et al.
Enhanced tumor growth inhibition by mesenchymal stem cells derived from iPSCs with targeted integration of interleukin24 into rDNA loci.
Oncotarget. 2017; 8(25):40791-40803 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Induced pluripotent stem cells (iPSCs) are a promising source of mesenchymal stem cells (MSCs) for clinical applications. In this study, we transformed human iPSCs using a non-viral vector carrying the IL24 transgene pHrn-IL24. PCR and southern blotting confirmed IL24 integration into the rDNA loci in four of 68 iPSC clones. We then differentiated a high expressing IL24-iPSC clone into MSCs (IL24-iMSCs) that showed higher expression of IL24 in culture supernatants and in cell lysates than control iMSCs. IL24-iMSCs efficiently differentiated into osteoblasts, chondrocytes and adipocytes. Functionally, IL24-iMSCs induced in vitro apoptosis in B16-F10 melanoma cells more efficiently than control iMSCs when co-cultured in Transwell assays. In vivo tumor xenograft studies in mice demonstrated that IL24-iMSCs inhibited melanoma growth more than control iMSCs did. Immunofluorescence and histochemical analysis showed larger necrotic areas and cell nuclear aggregation in tumors with IL24-iMSCs than control iMSCs, indicating that IL24-iMSCs inhibited tumor growth by inducing apoptosis. These findings demonstrate efficient transformation of iPSCs through gene targeting with non-viral vectors into a rDNA locus. The ability of these genetically modified MSCs to inhibit in vivo melanoma growth is suggestive of the clinical potential of autologous cell therapy in cancer.

Luo YH, Kuo YC, Tsai MH, et al.
Interleukin-24 as a target cytokine of environmental aryl hydrocarbon receptor agonist exposure in the lung.
Toxicol Appl Pharmacol. 2017; 324:1-11 [PubMed] Related Publications
Exposure to environmental aryl hydrocarbon receptor (AhR) agonists, such as halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), has great impacts on the development of various lung diseases. As emerging molecular targets for AhR agonists, cytokines may contribute to the inflammatory or immunotoxic effects of environmental AhR agonists. However, general cytokine expression may not specifically indicate environmental AhR agonist exposure. By comparing cytokine and chemokine expression profiles in human lung adenocarcinoma cell line CL5 treated with AhR agonists and the non-AhR agonist polychlorinated biphenyl (PCB) 39, we identified a target cytokine of environmental AhR agonist exposure of in the lungs. Thirteen cytokine and chemokine genes were altered in the AhR agonists-treated cells, but none were altered in the PCB39-treated cells. Interleukin (IL)-24 was the most highly induced gene among AhR-modulated cytokines. Cotreatment with AhR antagonist completely prevented IL-24 induction by AhR agonists in the CL5 cells. Knockdown AhR expression with short-hairpin RNA (shRNA) significantly reduced benzo[a]pyrene (BaP)-induced IL-24 mRNA levels. We further confirmed that gene transcription, but not mRNA stability, was involved in IL-24 upregulation by BaP. Particulate matter (PM) in the ambient air contains some PAHs and is reported to activate AhR. Oropharyngeal aspiration of PM significantly increased IL-24 levels in lung epithelia and in bronchoalveolar lavage fluid of mice 4weeks after treatment. Thus, our data suggests that IL-24 is a pulmonary exposure target cytokine of environmental AhR agonists.

Chang YS, Huang HD, Yeh KT, Chang JG
Identification of novel mutations in endometrial cancer patients by whole-exome sequencing.
Int J Oncol. 2017; 50(5):1778-1784 [PubMed] Related Publications
The aim of the present study was to identify genomic alterations in Taiwanese endometrial cancer patients. This information is vitally important in Taiwan, where endometrial cancer is the second most common gynecological cancer. We performed whole-exome sequencing on DNA from 14 tumor tissue samples from Taiwanese endometrial cancer patients. We used the Genome Analysis Tool kit software package for data analysis, and the dbSNP, Catalogue of Somatic Mutations in Cancer (COSMIC) and The Cancer Genome Atlas (TCGA) databases for comparisons. Variants were validated via Sanger sequencing. We identified 143 non-synonymous mutations in 756 canonical cancer-related genes and 1,271 non-synonymous mutations in non-canonical cancer-related genes in 14 endometrial samples. PTEN, KRAS and PIK3R1 were the most frequently mutated canonical cancer-related genes. Our results revealed nine potential driver genes (MAPT, IL24, MCM6, TSC1, BIRC2, CIITA, DST, CASP8 and NOTCH2) and 21 potential passenger genes (ARMCX4, IGSF10, VPS13C, DCT, DNAH14, TLN1, ZNF605, ZSCAN29, MOCOS, CMYA5, PCDH17, UGT1A8, CYFIP2, MACF1, NUDT5, JAKMIP1, PCDHGB4, FAM178A, SNX6, IMP4 and PCMTD1). The detected molecular aberrations led to putative activation of the mTOR, Wnt, MAPK, VEGF and ErbB pathways, as well as aberrant DNA repair, cell cycle control and apoptosis pathways. We characterized the mutational landscape and genetic alterations in multiple cellular pathways of endometrial cancer in the Taiwanese population.

Oikawa K, Mizusaki A, Takanashi M, et al.
PRG4 expression in myxoid liposarcoma maintains tumor cell growth through suppression of an antitumor cytokine IL-24.
Biochem Biophys Res Commun. 2017; 485(1):209-214 [PubMed] Related Publications
PRG4 is one of the downstream molecules of the myxoid liposarcoma (MLS)-specific fusion oncoproteins TLS-CHOP and EWS-CHOP. Exogenous PRG4 expression increases the tumorigenicity of cells injected in nude mice. The molecular functions of PRG4 in tumorigenesis and/or tumor progression of MLS cells, however, still remain unclear. In this report, we demonstrated that siRNA-mediated knockdown of PRG4 suppressed the growth of the MLS-derived cell lines 1955/91 and 2645/94. In addition, PRG4 knockdown promoted adipocytic differentiation in 1955/91 cells. Thus, PRG4 may play essential roles in MLS cell growth and have potential as a therapeutic target. On the other hand, our previous study has revealed that TLS-CHOP suppresses expression of an anti-tumor cytokine IL-24, contributing to tumor cell survival. In this study, we found that double knockdown of PRG4 and IL-24 did not inhibit MLS cell growth, and single knockdown of PRG4 remarkably increased IL-24 expression. These results suggest that the growth inhibitory effect of PRG4 knockdown is caused by induction of IL-24 expression, and PRG4 may contribute to maintain MLS cell growth through repression of IL-24 expression.

Panayotopoulou EG, Müller AK, Börries M, et al.
Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells.
Oncotarget. 2017; 8(28):45088-45104 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), induction of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve or paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced BV6 potency, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance.

Chen QN, Chen X, Chen ZY, et al.
Long intergenic non-coding RNA 00152 promotes lung adenocarcinoma proliferation via interacting with EZH2 and repressing IL24 expression.
Mol Cancer. 2017; 16(1):17 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
BACKGROUND: Numerous studies have shown that long non-coding RNAs (lncRNAs) behave as a novel class of transcript during multiple cancer processes, such as cell proliferation, apoptosis, migration, and invasion. LINC00152 is located on chromosome 2p11.2, and has a transcript length of 828 nucleotides. The biological role of LINC00152 in LAD(lung adenocarcinoma) remains unknown.
METHODS: Quantitative reverse transcription PCR(qRT-PCR) was used to detect LINC00152 expression in 60 human LAD tissues and paired normal tissues. In vitro and in vivo studies showed the biological function of LINC00152 in tumour progression. RNA transcriptome sequencing technology was performed to identify the downstream suppressor IL24(interleukin 24) which was further examined by qRT-PCR, western bolt and rescue experiments. RNA immunoprecipitation (RIP), RNA pulldown, and Chromatin immunoprecipitation (ChIP) assays were carried out to reveal the interaction between LINC00152, EZH2 and IL24.
RESULTS: LINC00152 expression was upregulated in 60 human LAD tissues and paired normal tissues. High levels of LINC00152 expression were correlated with advanced TNM stage, larger tumor size, and lymph node metastasis, as well as shorter survival time. Silencing of LINC00152 suppressed cell growth and induced cell apoptosis. LINC00152 knockdown altered the expression of many downstream genes, including IL24. LINC00152 could interact with EZH2 and inhibit IL24 transcription. Moreover, the ectopic expression of IL24 repressed cell proliferation and partly reversed LINC00152 overexpression-induced promotion of cell growth in LAD.
CONCLUSIONS: Our study reveals an oncogenic role for LINC00152 in LAD tumorigenesis, suggesting that it could be used as a therapeutic target in LAD treatment.

Sagara A, Karasawa T, Igarashi K, et al.
Controlled Secretion of the Anticancer Protein MDA-7 from Engineered Mesenchymal Stem Cells.
Biol Pharm Bull. 2017; 40(1):113-117 [PubMed] Related Publications
Mesenchymal stem cells (MSCs) have been explored as a "live" carrier of cytokines for targeted cancer therapy, but, in earlier reports in the literature, the secretion process of therapeutic cytokines was not regulated. The purpose of this study was to generate MSCs to conditionally secrete the melanoma differentiation-associated gene-7 (MDA-7) tumor-suppressor protein. To control the secretion of MDA-7 from MSCs, a well-established tetracycline-controlled transcriptional activation system was incorporated into MDA-7 plasmid. MDA-7 gene expression was induced in the engineered MSCs only in the presence of doxycycline, as characterized by quantitative reverse transcription (qRT)-PCR. Enzyme-linked immunosorbent assay (ELISA) also revealed that the MDA-7 protein was secreted from the engineered MSCs only after the cells had been exposed to doxycycline. Both recombinant human MDA-7 protein and the conditioned medium from the engineered MSCs in the presence of doxycycline significantly inhibited tube formation of human umbilical vascular endothelial cells (HUVECs), indicating that our system could be used for targeted, antiangiogenic therapy. Overall, this study provides useful information on the potential use of engineered MSCs for the controlled secretion of therapeutic proteins, in this case MDA-7, for targeted cancer therapy.

Hosseini E, Hosseini SY, Hashempour T, et al.
Effect of RGD coupled MDA-7/IL-24 on apoptosis induction in a hepatocellular carcinoma cell line.
Mol Med Rep. 2017; 15(1):495-501 [PubMed] Related Publications
The melanoma differentiation-associated gene‑7 (MDA-7) gene, also termed interleukin‑24 (IL‑24), is a tumor suppressor gene that induces apoptosis in a broad scope of malignant neoplastic cells. The apoptosis induction capacity of the MDA‑7/IL‑24 gene is partially associated with adhering to cognate receptors. The current study aimed to enhance the antitumor effect of IL‑24. The intrinsic signal sequence of IL-24 replaced with a fused artificial signal (secrecon)-RGD4C sequence and its impact was evaluated in HepG2 cells. The modified SP.RGD.IL‑24 and native IL‑24 cDNA sequences were cloned into the pcDNA3.1 expression vector. Subsequently, the expression level, secretion efficacy and targeting propensity of the modified SP.RGD.IL‑24 product compared with normal IL‑24 by were determined by enzyme‑linked immunosorbent assay. The constructs were then transfected into HepG2 and LX‑2 cells as tumor and normal hepatic cell lines, respectively. The expression level of the pro‑apoptotic DNA damage inducible transcript 3 (Gadd153) and BCL2 associated X apoptosis regulator (Bax) genes in the different groups were compared by reverse transcription-quantitative polymerase chain reaction. Additionally, the rate of apoptosis induction of modified and intact IL‑24 sequences was compared by flow cytometry analysis of cells following their propidium iodide/annexin V staining. SP.RGD-IL-24 protein was expressed and secreted in a similar manner to native IL‑24, however, the modified SP.RGD.IL-24 adhered to tumor cells more efficiently than IL‑24 (P<0.05). SP.RGD.IL‑24 significantly induced upregulation of Gadd153 and Bax in HepG2 cells compared with native IL‑24 (P<0.05). However, neither had a significant impact on the expression level of pro-apoptotic genes in LX‑2 cells. Flow cytometry analysis also indicated that modified SP.RGD.IL-24 induced apoptosis more than native IL‑24 in HepG2 cells (P<0.05). In conclusion, the novel generated RGD‑coupled IL-24 construct exhibited sufficient anticancer activity compared with the native IL‑24. The results of the current study provide novel insights for the future of cytokine targeting and indicates its potential capacity as a valuable candidate for gene therapy methods.

Pradhan AK, Talukdar S, Bhoopathi P, et al.
Cancer Res. 2017; 77(4):949-959 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Melanoma differentiation-associated gene-7/IL-24 (

Panneerselvam J, Srivastava A, Muralidharan R, et al.
IL-24 modulates the high mobility group (HMG) A1/miR222 /AKT signaling in lung cancer cells.
Oncotarget. 2016; 7(43):70247-70263 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
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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