Bio

Honors & Awards


  • National Fellowships, National Research Foundation of Korea (08 / 2007 ~ 07 / 2008)
  • National Scholarships, Gwangju Institute of Science and Technology (03 / 2004 ~ 02 / 2006)
  • Dean?s Lists, Sungkyunkwan University (09 / 1999 ~ 12 / 2002)

Professional Education


  • Doctor of Philosophy, Ohio State University (2015)
  • Master of Science, Gwangju Institute of Science and Technology (2006)
  • Bachelor of Science, Sung Kyun Kwan University (2003)

Stanford Advisors


Publications

All Publications


  • miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC. Nature communications Jeon, Y., Kim, T., Park, D., Nuovo, G. J., Rhee, S., Joshi, P., Lee, B., Jeong, J., Suh, S., Grotzke, J. E., Kim, S., Song, J., Sim, H., Kim, Y., Peng, Y., Jeong, Y., Garofalo, M., Zanesi, N., Kim, J., Liang, G., Nakano, I., Cresswell, P., Nana-Sinkam, P., Cui, R., Croce, C. M. 2018; 9 (1): 5110

    Abstract

    Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6alpha-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1alpha and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.

    View details for PubMedID 30504895

  • Comparative expression profiling of testis-enriched genes regulated during the development of spermatogonial cells PLOS ONE Ahn, J., Park, Y., Chen, P., Lee, T. J., Jeon, Y., Croce, C. M., Suh, Y., Hwang, S., Kwon, W., Pang, M., Kim, C., Lee, S. S., Lee, K. 2017; 12 (4)

    Abstract

    The testis has been identified as the organ in which a large number of tissue-enriched genes are present. However, a large portion of transcripts related to each stage or cell type in the testis still remains unknown. In this study, databases combined with confirmatory measurements were used to investigate testis-enriched genes, localization in the testis, developmental regulation, gene expression profiles of testicular disease, and signaling pathways. Our comparative analysis of GEO DataSets showed that 24 genes are predominantly expressed in testis. Cellular locations of 15 testis-enriched proteins in human testis have been identified and most of them were located in spermatocytes and round spermatids. Real-time PCR revealed that expressions of these 15 genes are significantly increased during testis development. Also, an analysis of GEO DataSets indicated that expressions of these 15 genes were significantly decreased in teratozoospermic patients and polyubiquitin knockout mice, suggesting their involvement in normal testis development. Pathway analysis revealed that most of those 15 genes are implicated in various sperm-related cell processes and disease conditions. This approach provides effective strategies for discovering novel testis-enriched genes and their expression patterns, paving the way for future characterization of their functions regarding infertility and providing new biomarkers for specific stages of spematogenesis.

    View details for DOI 10.1371/journal.pone.0175787

    View details for Web of Science ID 000399874800055

    View details for PubMedID 28414809

  • APIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis. Oncotarget Hong, S. H., Lee, W. J., Kim, Y. D., Kim, H., Jeon, Y. J., Lim, B., Cho, D. H., Heo, W. D., Yang, D. H., Kim, C. Y., Yang, H. K., Yang, J. K., Jung, Y. K. 2016

    Abstract

    Despite the fact that the epidermal growth factor (EGF) family member ERBB3 (HER3) is deregulated in many cancers, the list of ERBB3-interacting partners remains limited. Here, we report that the Apaf-1-interacting protein (APIP) stimulates heregulin-?1 (HRG-?1)/ERBB3-driven cell proliferation and tumorigenesis. APIP levels are frequently increased in human gastric cancers and gastric cancer-derived cells. Cell proliferation and tumor formation are repressed by APIP downregulation and stimulated by its overexpression. APIP's role in the ERBB3 pathway is not associated with its functions within the methionine salvage pathway. In response to HRG-?1, APIP binds to the ERBB3 receptor, leading to an enhanced binding of ERBB3 and ERBB2 that results in sustained activations of ERK1/2 and AKT protein kinases. Furthermore, HRG-?1/ERBB3-dependent signaling is gained in APIP transgenic mouse embryonic fibroblasts (MEFs), but not lost in Apip-/- MEFs. Our findings offer compelling evidence that APIP plays an essential role in ERBB3 signaling as a positive regulator for tumorigenesis, warranting future development of therapeutic strategies for ERBB3-driven gastric cancer.

    View details for DOI 10.18632/oncotarget.7802

    View details for PubMedID 26942872

  • ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5. Cancer cell Sun, H. L., Cui, R., Zhou, J., Teng, K. Y., Hsiao, Y. H., Nakanishi, K., Fassan, M., Luo, Z., Shi, G., Tili, E., Kutay, H., Lovat, F., Vicentini, C., Huang, H. L., Wang, S. W., Kim, T., Zanesi, N., Jeon, Y. J., Lee, T. J., Guh, J. H., Hung, M. C., Ghoshal, K., Teng, C. M., Peng, Y., Croce, C. M. 2016; 30 (5): 723?36

    Abstract

    MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.

    View details for PubMedID 27846390

  • MicroRNA-224 is implicated in lung cancer pathogenesis through targeting caspase-3 and caspase-7 ONCOTARGET Cui, R., Kim, T., Fassan, M., Meng, W., Sun, H., Jeon, Y., Vicentini, C., Tili, E., Peng, Y., Scarpa, A., Liang, G., Zhang, Y. K., Chakravarti, A., Croce, C. M. 2015; 6 (26): 21802-21815

    Abstract

    We recently reported that miR-224 was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues, in particular in resected NSCLC metastasis. We further demonstrated that miR-224 functions as an oncogene in NSCLC by directly targeting TNFAIP1 and SMAD4. However, the biological functions of miR-224 in NSCLC are controversial and underlying mechanisms of miR-224 in the progression and metastasis of lung cancer remain to be further explored. Here we report that caspase3 (CASP3) and caspase7 (CASP7) are previously unidentified targets of miR-224 in NSCLC, and that miR-224 promotes lung cancer cells proliferation and migration in part by directly targeting CASP7 and down-regulating its expression. In addition, miR-224 attenuated TNF-? induced apoptosis by direct targeting of CASP3 resulting in reduction of cleaved PARP1 expression in lung cancer cells. Furthermore, the expression of miR-224 negatively correlates with the expression of CASP7 and CASP3 in tissue samples from patients with lung cancer. Finally, we found that activated NF-?B signaling is involved in the regulation of miR-224 expression in lung cancer. Our study provides new insight in understanding of oncogenic role of miR-224 in the lung cancer pathogenesis and suggests that NF-?B/miR-224/CASP3, 7 pathway could be a putative therapeutic target in lung cancer.

    View details for DOI 10.18632/oncotarget.5224

    View details for PubMedID 26307684

  • The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells CELL DEATH AND DIFFERENTIATION Kim, S., Kim, E., Hitomi, M., Oh, S., Jin, X., Jeon, H., Beck, S., Jin, X., Kim, J., Park, C. G., Chang, S., Yin, J., Kim, T., Jeon, Y., Song, J., Lim, Y. C., Lathia, J. D., Nakano, I., Kim, H. 2015; 22 (9): 1517-1525

    Abstract

    Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared with the differentiated progeny cells. LMO2 is required for GSC proliferation both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse premalignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in GBMs.

    View details for DOI 10.1038/cdd.2015.7

    View details for Web of Science ID 000359295300011

    View details for PubMedID 25721045

  • MYC-repressed long noncoding RNAs antagonize MYC-induced cell proliferation and cell cycle progression ONCOTARGET Kim, T., Cui, R., Jeon, Y., Fadda, P., Alder, H., Croce, C. M. 2015; 6 (22): 18780-18789

    Abstract

    The transcription factor MYC is a proto-oncogene regulating cell proliferation, cell cycle, apoptosis and metabolism. The recent identification of MYC-regulated long noncoding RNAs (lncRNAs) expands our knowledge of the role of lncRNAs in MYC functions. Here, we identify MYC-repressed lncRNAs named MYCLo-4, -5 and -6 by comparing 3 categories of lncRNAs (downregulated in highly MYC-expressing colorectal cancer, up-regulated by MYC knockdown in HCT116, upregulated by MYC knockdown in RKO). The MYC-repressed MYCLos are implicated in MYC-modulated cell proliferation through cell cycle regulation. By screening cell cycle-related genes regulated by MYC and the MYC-repressed MYCLos, we identified the MYC-repressed gene GADD45A as a target gene of the MYC-repressed MYCLos such as MYCLo-4 and MYCLo-6.

    View details for PubMedID 26003165

  • MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cui, R., Meng, W., Sun, H., Kim, T., Ye, Z., Fassan, M., Jeon, Y., Li, B., Vicentini, C., Peng, Y., Lee, T. J., Luo, Z., Liu, L., Xu, D., Tili, E., Jin, V., Middleton, J., Chakravarti, A., Lautenschlaeger, T., Croce, C. M. 2015; 112 (31): E4288-E4297

    Abstract

    Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNF?-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.

    View details for DOI 10.1073/pnas.1502068112

    View details for PubMedID 26187928

  • MicroRNA-148a reduces tumorigenesis and increases TRAIL-induced apoptosis in NSCLC PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Joshi, P., Jeon, Y., Lagana, A., Middleton, J., Secchiero, P., Garofalo, M., Croce, C. M. 2015; 112 (28): 8650-8655

    Abstract

    Nonsmall cell lung cancer (NSCLC) is one of the leading causes of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells without inducing significant toxicity in normal cells. However, several carcinomas, including lung cancer, remain resistant to TRAIL. MicroRNAs (miRNAs) are small noncoding RNAs of ? 24 nt that block mRNA translation and/or negatively regulate its stability. They are often aberrantly expressed in cancer and have been implicated in increasing susceptibility or resistance to TRAIL-induced apoptosis by inhibiting key functional proteins. Here we show that miR-148a is down-regulated in cells with acquired TRAIL-resistance compared with TRAIL-sensitive cells. Enforced expression of miR-148a sensitized cells to TRAIL and reduced lung tumorigenesis in vitro and in vivo through the down-modulation of matrix metalloproteinase 15 (MMP15) and Rho-associated kinase 1 (ROCK1). These findings suggest that miR-148a acts as a tumor suppressor and might have therapeutic application in the treatment of NSCLC.

    View details for DOI 10.1073/pnas.1500886112

    View details for Web of Science ID 000357878700048

    View details for PubMedID 26124099

  • A set of NF-kappa B-regulated microRNAs induces acquired TRAIL resistance in Lung cancer PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Jeon, Y., Middleton, J., Kim, T., Lagana, A., Piovan, C., Secchiero, P., Nuovo, G. J., Cui, R., Joshi, P., Romano, G., Di Leva, G., Lee, B., Sun, H., Kim, Y., Fadda, P., Alder, H., Garofalo, M., Croce, C. M. 2015; 112 (26): E3355-E3364

    Abstract

    TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-?B, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-?B, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-?B inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.

    View details for DOI 10.1073/pnas.1504630112

    View details for PubMedID 26080425

  • Role of MYC-Regulated Long Noncoding RNAs in Cell Cycle Regulation and Tumorigenesis JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Kim, T., Jeon, Y., Cui, R., Lee, J., Peng, Y., Kim, S., Tili, E., Alder, H., Croce, C. M. 2015; 107 (4)

    Abstract

    The functions of long noncoding RNAs (lncRNAs) have been identified in several cancers, but the roles of lncRNAs in colorectal cancer (CRC) are less well understood. The transcription factor MYC is known to regulate lncRNAs and has been implicated in cancer cell proliferation and tumorigenesis.CRC cells and tissues were profiled to identify lncRNAs differentially expressed in CRC, from which we further selected MYC-regulated lncRNAs. We used luciferase promoter assay, ChIP, RNA pull-down assay, deletion mapping assay, LC-MS/MS and RNA immunoprecipitation to determine the mechanisms of MYC regulation of lncRNAs. Moreover, soft agar assay and in vivo xenograft experiments (four athymic nude mice per group) provided evidence of MYC-regulated lncRNAs in cancer cell transformation and tumorigenesis. The Kaplan-Meier method was used for survival analyses. All statistical tests were two-sided.We identified lncRNAs differentially expressed in CRC (P < .05, greater than two-fold) and verified four lncRNAs upregulated and two downregulated in CRC cells and tissues. We further identified MYC-regulated lncRNAs, named MYCLos. The MYC-regulated MYCLos may function in cell proliferation and cell cycle by regulating MYC target genes such as CDKN1A (p21) and CDKN2B (p15), suggesting new regulatory mechanisms of MYC-repressed target genes through lncRNAs. RNA binding proteins including HuR and hnRNPK are involved in the function of MYCLos by interacting with MYCLo-1 and MYCLo-2, respectively. Knockdown experiments also showed that MYCLo-2, differentially expressed not only in CRC but also in prostate cancer, has a role in cancer transformation and tumorigenesis.Our results provide novel regulatory mechanisms in MYC function through lncRNAs and new potential lncRNA targets of CRC.

    View details for DOI 10.1093/jnci/dju505

    View details for Web of Science ID 000355082500003

    View details for PubMedID 25663692

  • MicroRNAs in lung cancer. World journal of methodology Joshi, P., Middleton, J., Jeon, Y., Garofalo, M. 2014; 4 (2): 59-72

    Abstract

    MicroRNAs have become recognized as key players in the development of cancer. They are a family of small non-coding RNAs that can negatively regulate the expression of cancer-related genes by sequence-selective targeting of mRNAs, leading to either mRNA degradation or translational repression. Lung cancer is the leading cause of cancer-related death worldwide with a substantially low survival rate. MicroRNAs have been confirmed to play roles in lung cancer development, epithelial-mesenchymal transition and response to therapy. They are also being studied for their future use as diagnostic and prognostic biomarkers and as potential therapeutic targets. In this review we focus on the role of dysregulated microRNA expression in lung tumorigenesis. We also discuss the role of microRNAs in therapeutic resistance and as biomarkers. We further look into the progress made and challenges remaining in using microRNAs for therapy in lung cancer.

    View details for DOI 10.5662/wjm.v4.i2.59

    View details for PubMedID 25332906

  • Long-range interaction and correlation between MYC enhancer and oncogenic long noncoding RNA CARLo-5 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kim, T., Cui, R., Jeon, Y., Lee, J., Lee, J. H., Sim, H., Park, J. K., Fadda, P., Tili, E., Nakanishi, H., Huh, M., Kim, S., Cho, J. H., Sung, B. H., Peng, Y., Lee, T. J., Luo, Z., Sun, H., Wei, H., Alder, H., Oh, J. S., Shim, K. S., Ko, S., Croce, C. M. 2014; 111 (11): 4173-4178

    Abstract

    The mechanism by which the 8q24 MYC enhancer region, including cancer-associated variant rs6983267, increases cancer risk is unknown due to the lack of protein-coding genes at 8q24.21. Here we report the identification of long noncoding RNAs named cancer-associated region long noncoding RNAs (CARLos) in the 8q24 region. The expression of one of the long noncoding RNAs, CARLo-5, is significantly correlated with the rs6983267 allele associated with increased cancer susceptibility. We also found the MYC enhancer region physically interacts with the active regulatory region of the CARLo-5 promoter, suggesting long-range interaction of MYC enhancer with the CARLo-5 promoter regulates CARLo-5 expression. Finally, we demonstrate that CARLo-5 has a function in cell-cycle regulation and tumor development. Overall, our data provide a key of the mystery of the 8q24 gene desert.

    View details for DOI 10.1073/pnas.1400350111

    View details for Web of Science ID 000333027900066

    View details for PubMedID 24594601

  • Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Peng, Y., Dai, Y., Hitchcock, C., Yang, X., Kassis, E. S., Liu, L., Luo, Z., Sun, H., Cui, R., Wei, H., Kim, T., Lee, T. J., Jeon, Y., Nuovo, G. J., Volinia, S., He, Q., Yu, J., Nana-Sinkam, P., Croce, C. M. 2013; 110 (37): 15043-15048

    Abstract

    MicroRNAs (miRNAs) are small 19- to 24-nt noncoding RNAs that have the capacity to regulate fundamental biological processes essential for cancer initiation and progression. In cancer, miRNAs may function as oncogenes or tumor suppressors. Here, we conducted global profiling for miRNAs in a cohort of stage 1 nonsmall cell lung cancers (n = 81) and determined that miR-486 was the most down-regulated miRNA in tumors compared with adjacent uninvolved lung tissues, suggesting that miR-486 loss may be important in lung cancer development. We report that miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo. Our findings support the role for miR-486 loss in lung cancer and suggest a potential biological link to p53.

    View details for DOI 10.1073/pnas.1307107110

    View details for Web of Science ID 000324125100055

    View details for PubMedID 23980150

  • MiR-34a/c-Dependent PDGFR-?/? Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer. PloS one Garofalo, M., Jeon, Y. J., Nuovo, G. J., Middleton, J., Secchiero, P., Joshi, P., Alder, H., Nazaryan, N., Di Leva, G., Romano, G., Crawford, M., Nana-Sinkam, P., Croce, C. M. 2013; 8 (6): e67581

    Abstract

    Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-? and PDGFR-?), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-?/? and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-?/? by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells.

    View details for DOI 10.1371/journal.pone.0067581

    View details for PubMedID 23805317

  • Regulation in the targeting of TRAIL receptor 1 to cell surface via GODZ for TRAIL sensitivity in tumor cells CELL DEATH AND DIFFERENTIATION Oh, Y., Jeon, Y., Hong, G., Kim, I., Woo, H., Jung, Y. 2012; 19 (7): 1196-1207

    Abstract

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), promote the selective clearing of various malignancies by inducing apoptosis, holding the promise as a potent therapeutic agent for anticancer. Though DR4 and DR5 have high sequence similarity, differential regulation of both receptors in human tumor cells remains largely unexplored. Here, we repot that golgi-specific Asp-His-His-Cys (DHHC) zinc finger protein (GODZ) regulates TRAIL/DR4-mediated apoptosis. Using the SOS protein recruitment-yeast two-hybrid screening, we isolated GODZ that interacted with the death domain of DR4. GODZ binds to DR4, but not to DR5, through the DHHC and the C-terminal transmembrane domain. Expression level of GODZ affects apoptosis of tumor cells triggered by TRAIL, but not that induced by TNF-?/cycloheximide (CHX) or DNA-damaging drugs. In parallel, GODZ functions to localize DR4 to the plasma membrane (PM) via DHHC motif. Also, introduction of mutation into the cysteine-rich motif of DR4 results in its mistargeting and attenuates TRAIL- or GODZ-mediated apoptosis. Interestingly, GODZ expression is highly downregulated in Hep-3B tumor cells, which show resistance to TRAIL. However, reconstitution of GODZ expression enhances the targeting of DR4 to cell surface and sensitizes Hep-3B cells to TRAIL. Taken together, these data establish that GODZ is a novel DR4-selective regulator responsible for targeting of DR4 to the PM, and thereby for TRAIL-induced apoptosis.

    View details for DOI 10.1038/cdd.2011.209

    View details for Web of Science ID 000305295300011

    View details for PubMedID 22240897

  • MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Suh, S., Yoo, J. Y., Nuovo, G. J., Jeon, Y., Kim, S., Lee, T. J., Kim, T., Bakacs, A., Alder, H., Kaur, B., Aqeilan, R. I., Pichiorri, F., Croce, C. M. 2012; 109 (14): 5316-5321

    Abstract

    MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs by p53-dependent negative regulation of their transcriptional regulators, E2F1 and MYC. However, miR-25 and -32 result in p53 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR (mammalian target of rapamycin) pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Thus, there is a recurrent autoregulatory circuit involving expression of p53, E2F1, and MYC to regulate the expression of miR-25 and -32, which are miRNAs that, in turn, control p53 accumulation. Significantly, overexpression of transfected miR-25 and -32 in glioblastoma multiforme cells inhibited growth of the glioblastoma multiforme cells in mouse brain in vivo. The results define miR-25 and -32 as positive regulators of p53, underscoring their role in tumorigenesis in glioblastoma.

    View details for DOI 10.1073/pnas.1202465109

    View details for Web of Science ID 000302294700046

    View details for PubMedID 22431589

  • EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nature medicine Garofalo, M., Romano, G., Di Leva, G., Nuovo, G., Jeon, Y., Ngankeu, A., Sun, J., Lovat, F., Alder, H., Condorelli, G., Engelman, J. A., Ono, M., Rho, J. K., Cascione, L., Volinia, S., Nephew, K. P., Croce, C. M. 2012; 18 (1): 74-82

    Abstract

    The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ? (PKC-?) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.

    View details for DOI 10.1038/nm.2577

    View details for PubMedID 22157681

  • p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2 JOURNAL OF EXPERIMENTAL MEDICINE Kim, T., Veronese, A., Pichiorri, F., Lee, T. J., Jeon, Y., Volinia, S., Pineau, P., Marchio, A., Palatini, J., Suh, S., Alder, H., Liu, C., Dejean, A., Croce, C. M. 2011; 208 (5): 875-883

    Abstract

    p53 suppresses tumor progression and metastasis. Epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis. The transcription factors ZEB1 and ZEB2 promote EMT. Here, we show that p53 suppresses EMT by repressing expression of ZEB1 and ZEB2. By profiling 92 primary hepatocellular carcinomas (HCCs) and 9 HCC cell lines, we found that p53 up-regulates microRNAs (miRNAs), including miR-200 and miR-192 family members. The miR-200 family members transactivated by p53 then repress ZEB1/2 expression. p53-regulated miR-192 family members also repress ZEB2 expression. Inhibition or overexpression of the miRNAs affects p53-regulated EMT by altering ZEB1 and ZEB2 expression. Our findings indicate that p53 can regulate EMT, and that p53-regulated miRNAs are critical mediators of p53-regulated EMT.

    View details for DOI 10.1084/jem.20110235

    View details for Web of Science ID 000291425400001

    View details for PubMedID 21518799

  • Ribosomal protein S6 is a selective mediator of TRAIL-apoptotic signaling ONCOGENE Jeon, Y., Kim, I. K., Hong, S., Nan, H., Kim, H., Lee, H., Masuda, E. S., Meyuhas, O., Oh, B., Jung, Y. 2008; 27 (31): 4344-4352

    Abstract

    TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potent inducer of apoptosis in tumor cells and holds a promise as a therapeutic agent against cancer. To elucidate the death signaling evoked by TRAIL, we performed a functional genetic screening and rescued TRAIL-resistant Jurkat clones harboring ribosomal protein S6 (rpS6) cDNA in anti-sense frame. Reduction of rpS6 expression in Jurkat and HeLa cells attenuated apoptosis induced by TRAIL, but not those by other cell death signals, including tumor necrosis factor-alpha and cycloheximide, etoposide, doxorubicin, tunicamycin and staurosporine. Death receptor (DR) 4, but not DR5, was downregulated in rpS6 knockdown cells. Conversely, the sensitivity to TRAIL was increased by the ectopic expression of wild-type rpS6 and further by phospho-defective rpS6 mutant (S6-SS235,6AA), but not by phospho-mimic rpS6 mutant (S6-SS235,6DD). Also, unphosphorylatable rpS6 knock-in mouse embryo fibroblasts (rpS6(P-/-) MEFs) were more sensitive to TRAIL than control MEFs. In addition, SKHep-1 tumor cells, which express less phospho-rpS6 and are more sensitive to TRAIL than other tumor cells, became effectively desensitized to TRAIL after rpS6 knockdown. These results suggest that rpS6, especially in its unphosphorylated form, is a selective mediator of TRAIL-induced apoptosis.

    View details for DOI 10.1038/onc.2008.73

    View details for Web of Science ID 000257691100009

    View details for PubMedID 18362888

  • AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10 NATURE CELL BIOLOGY Lee, H., Pyo, J., Oh, Y., Kim, H., Hong, S., Jeon, Y., Kim, H., Cho, D., Woo, H., Song, S., Nam, J., Kim, H. J., Kim, K., Jung, Y. 2007; 9 (11): 1303-U176

    Abstract

    Mitochondrial proteins function as essential regulators in apoptosis. Here, we show that mitochondrial adenylate kinase 2 (AK2) mediates mitochondrial apoptosis through the formation of an AK2-FADD-caspase-10 (AFAC10) complex. Downregulation of AK2 attenuates etoposide- or staurosporine-induced apoptosis in human cells, but not that induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) or Fas ligand (FasL). During intrinsic apoptosis, AK2 translocates to the cytoplasm, whereas this event is diminished in Apaf-1 knockdown cells and prevented by Bcl-2 or Bcl-X(L). Addition of purified AK2 protein to cell extracts first induces activation of caspase-10 via FADD and subsequently caspase-3 activation, but does not affect caspase-8. AFAC10 complexes are detected in cells undergoing intrinsic cell death and AK2 promotes the association of caspase-10 with FADD. In contrast, AFAC10 complexes are not detected in several etoposide-resistant human tumour cell lines. Taken together, these results suggest that, acting in concert with FADD and caspase-10, AK2 mediates a novel intrinsic apoptotic pathway that may be involved in tumorigenesis.

    View details for DOI 10.1038/ncb1650

    View details for Web of Science ID 000250659600016

    View details for PubMedID 17952061

  • Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin HUMAN MOLECULAR GENETICS Chang, J., Choi, H., Kim, H., Jo, D., Jeon, Y., Noh, J., Park, W. J., Jung, Y. 2007; 16 (3): 317-326

    Abstract

    Calsenilin/DREAM/KChIP3, a neuronal Ca(2+)-binding protein, has multifunctions in nucleus and cytosol. Here, we identified CLN3 as a calsenilin-binding partner whose mutation or deletion is observed in Batten disease. In vitro binding and immunoprecipitation assays show that calsenilin interacts with the C-terminal region of CLN3 and the increase of Ca(2+) concentration in vitro and in cells causes significant dissociation of calsenilin from CLN3. Ectopic expression of CLN3 or its deletion mutant containing only the C-terminus (153-438) and capable of binding to calsenilin suppresses thapsigargin or A23187-induced death of neuronal cells. In contrast, CLN3 deletion mutant containing the N-terminus (1-153) or (1-263), which is frequently found in Batten disease, induces the perturbation of Ca(2+) transient and fails to inhibit the cell death. In addition, the expression of calsenilin is increased in the brain tissues of CLN3 knock-out mice and SH-SY5Y/CLN3 knock-down cells. Down-regulation of CLN3 expression sensitizes SH-SY5Y cells to thapsigargin or A23187. However, additional decrease of calsenilin expression rescues the sensitivity of SH-SY5Y/CLN3 knock-down cells to Ca(2+)-mediated cell death. These results suggest that the vulnerability of CLN3 knock-out or CLN3 deletion (1-153)-expressing neuronal cells to Ca(2+)-induced cell death may be mediated by calsenilin.

    View details for DOI 10.1093/hmg/ddl466

    View details for Web of Science ID 000244126000008

    View details for PubMedID 17189291

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