Ding Ling Wen
Email Address
csidlw@nus.edu.sg
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Publication The characterization of SaPIN2b, a plant trichome-localized proteinase inhibitor from Solanum americanum(2012) Luo, M; Ding, L.-W; Ge, Z.-J; Wang, Z.-Y; Hu, B.-L; Yang, X.-B; Sun, Q.-Y; Xu, Z.-F; CANCER SCIENCE INSTITUTE OF SINGAPOREProteinase inhibitors play an important role in plant resistance of insects and pathogens. In this study, we characterized the serine proteinase inhibitor SaPIN2b, which is constitutively expressed in Solanum americanum trichomes and contains two conserved motifs of the proteinase inhibitor II (PIN2) family. The recombinant SaPIN2b (rSaPIN2b), which was expressed in Escherichia coli, was demonstrated to be a potent proteinase inhibitor against a panel of serine proteinases, including subtilisin A, chymotrypsin and trypsin. Moreover, rSaPIN2b also effectively inhibited the proteinase activities of midgut trypsin-like proteinases that were extracted from the devastating pest Helicoverpa armigera. Furthermore, the overexpression of SaPIN2b in transgenic tobacco plants resulted in enhanced resistance against H. armigera. Taken together, our results demonstrated that SaPIN2b is a potent serine proteinase inhibitor that may act as a protective protein in plant defense against insect attacks. © 2012 by the authors; licensee MDPI, Basel, Switzerland.Publication Integrative Epigenomic Analysis of Transcriptional Regulation of Human CircRNAs(Frontiers Media S.A., 2021-01-25) Li, Xue-Cang; Tang, Zhi-Dong; Peng, Li; Li, Yan-Yu; Qian, Feng-Cui; Zhao, Jian-Mei; Ding, Ling-Wen; Du, Xiao-Juan; Li, Meng; Zhang, Jian; Bai, Xue-Feng; Zhu, Jiang; Feng, Chen-Chen; Wang, Qiu-Yu; Pan, Jian; Li, Chun-Quan; CANCER SCIENCE INSTITUTE OF SINGAPORECircular RNAs (circRNAs) are evolutionarily conserved and abundant non-coding RNAs whose functions and regulatory mechanisms remain largely unknown. Here, we identify and characterize an epigenomically distinct group of circRNAs (TAH-circRNAs), which are transcribed to a higher level than their host genes. By integrative analysis of cistromic and transcriptomic data, we find that compared with other circRNAs, TAH-circRNAs are expressed more abundantly and have more transcription factors (TFs) binding sites and lower DNA methylation levels. Concordantly, TAH-circRNAs are enriched in open and active chromatin regions. Importantly, ChIA-PET results showed that 23–52% of transcription start sites (TSSs) of TAH-circRNAs have direct interactions with cis-regulatory regions, strongly suggesting their independent transcriptional regulation from host genes. In addition, we characterize molecular features of super-enhancer-driven circRNAs in cancer biology. Together, this study comprehensively analyzes epigenomic characteristics of circRNAs and identifies a distinct group of TAH-circRNAs that are independently transcribed via enhancers and super-enhancers by TFs. These findings substantially advance our understanding of the regulatory mechanism of circRNAs and may have important implications for future investigations of this class of non-coding RNAs. © Copyright © 2021 Li, Tang, Peng, Li, Qian, Zhao, Ding, Du, Li, Zhang, Bai, Zhu, Feng, Wang, Pan and Li.Publication PIAS4 is an activator of hypoxia signalling via VHL suppression during growth of pancreatic cancer cells(2013-10-01) Chien, W.; Lee, K.L.; Ding, L.W.; Wuensche, P.; Kato, H.; Doan, N.B.; Poellinger, L.; Said, J.W.; Koeffler, H.P.; CANCER SCIENCE INSTITUTE OF SINGAPOREBackground:The PIAS4 protein belongs to the family of protein inhibitors of activated STAT, but has since been implicated in various biological activities including the post-translational modification known as sumoylation. In this study, we explored the roles of PIAS4 in pancreatic tumourigenesis.Methods:The expression levels of PIAS4 in pancreatic cancer cells were examined. Cell proliferation and invasion was studied after overexpression and gene silencing of PIAS4. The effect of PIAS4 on hypoxia signalling was investigated.Results:The protein was overexpressed in pancreatic cancer cells compared with the normal pancreas. Gene silencing by PIAS4 small interfering RNA (siRNA) suppressed pancreatic cancer cell growth and overexpression of PIAS4 induced expression of genes related to cell growth. The overexpression of PIAS4 is essential for the regulation of the hypoxia signalling pathway. PIAS4 interacts with the tumour suppressor von Hippel-Lindau (VHL) and leads to VHL sumoylation, oligomerization, and impaired function. Pancreatic cancer cells (Panc0327, MiaPaCa2) treated with PIAS4 siRNA suppressed expression of the hypoxia-inducible factor hypoxia-inducible factor 1 alpha and its target genes JMJD1A, VEGF, and STAT3.Conclusion:Our study elucidates the role of PIAS4 in the regulation of pancreatic cancer cell growth, where the suppression of its activity represents a novel therapeutic target for pancreatic cancers. © 2013 Cancer Research UK.Publication FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites(Ivyspring International Publisher, 2023-01-01) Thuya, WL; Kong, LR; Syn, NL; Ding, LW; Cheow, ESH; Wong, RTX; Wang, T; Goh, RMWJ; Song, H; Jayasinghe, MK; Le, MTN; Hu, JC; Yong, WP; Lee, SC; Wong, ALA; Sethi, G; Hung, HT; Ho, PCL; Thiery, JP; Sze, SK; Guo, T; Soo, RA; Yang, H; Lim, YC; Wang, L; Goh, BC; Dr Li Ren Kong; PHARMACOLOGY; BIOLOGY; MEDICINE; CANCER SCIENCE INSTITUTE OF SINGAPORE; BIOCHEMISTRY; PHARMACYRationale: Metastasis is a complex process with a molecular underpinning that remains unclear. We hypothesize that cargo proteins conducted by extracellular vesicles (EVs) released from tumors may confer growth and metastasis potential on recipient cells. Here, we report that a cytokine-like secreted protein, FAM3C, contributes to late-stage lung tumor progression. Methods: EV protein profiling was conducted with an unbiased proteomic mass spectrometry analysis on non-small cell lung cancer (NSCLC) and normal lung fibroblast cell lines. Expression of FAM3C was confirmed in a panel of NSCLC cell lines, and correlated to the invasive and metastatic potentials. Functional phenotype of endogenous FAM3C and tumor-derived EVs (TDEs) were further investigated using various biological approaches in RNA and protein levels. Metastasis potential of TDEs secreted by FAM3C-overexpressing carcinoma cells was validated in mouse models. Results: Transcriptomic meta-analysis of pan-cancer datasets confirmed the overexpression of FAM3C - a gene encoding for interleukin-like EMT inducer (ILEI) - in NSCLC tumors, with strong association with poor patient prognosis and cancer metastasis. Aberrant expression of FAM3C in lung carcinoma cells enhances cellular transformation and promotes distant lung tumor colonization. In addition, higher FAM3C concentrations were detected in EVs extracted from plasma samples of NSCLC patients compared to those of healthy subjects. More importantly, we defined a hitherto-unknown mode of microenvironmental crosstalk involving FAM3C in EVs, whereby the delivery and uptake of FAM3C via TDEs enhances oncogenic signaling - in recipient cells that phenocopies the cell-endogenous overexpression of FAM3C. The oncogenicity transduced by FAM3C is executed via a novel interaction with the Ras-related protein RalA, triggering the downstream activation of the Src/Stat3 signaling cascade. Conclusions: Our study describes a novel mechanism for FAM3C-driven carcinogenesis and shed light on EV FAM3C as a driver for metastatic lung tumors that could be exploited for cancer therapeutics.Publication Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia (vol 30, pg 1672, 2016)(NATURE PUBLISHING GROUP, 2016-12-01) Madan, V; Shyamsunder, P; Han, L; Mayakonda, A; Nagata, Y; Sundaresan, J; Kanojia, D; Yoshida, K; Ganesan, S; Hattori, N; Fulton, N; Tan, KT; Alpermann, T; Kuo, MC; Rostami, S; Matthews, J; Sanada, M; Liu, L-Z; Shiraishi, Y; Miyano, S; Chendamarai, E; Hou, HA; Malnassy, G; Ma, T; Garg, M; Ding, LW; Sun, QY; Chien, W; Ikezoe, T; Lill, M; Biondi, A; Larson, RA; Powell, BL; Lubbert, M; Chng, WJ; Tien, HF; Heuser, M; Ganser, A; Koren-Michowitz, M; Kornblau, SM; Kantarjian, HM; Nowak, D; Hofmann, WK; Yang, H; Stock, W; Ghavamzadeh, A; Alimoghaddam, K; Haferlach, T; Ogawa, S; Shih, LY; Mathews, V; Koeffler, HP; Prof Wee Joo Chng; MEDICINE; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); CANCER SCIENCE INSTITUTE OF SINGAPOREPublication Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers(2013-04-09) Lin, D.-C.; Xu, L.; Ding, L.-W.; Sharma, A.; Liu, L.-Z.; Yang, H.; Tan, P.; Vadgama, J.; Karlan, B.Y.; Lester, J.; Urban, N.; Schummer, M.; Doan, N.; Said, J.W.; Sun, H.; Walsh, M.; Thomas, C.J.; Patel, P.; Yin, D.; Chan, D.; Phillip Koeffler, H.; CANCER SCIENCE INSTITUTE OF SINGAPOREDiscovery of cancer genes through interrogation of genomic dosage is one of the major approaches in cancer research. In this study, we report that phosphodiesterase subtype 4D(PDE4D) gene was homozygously deleted in 198 cases of 5,569 primary solid tumors (3.56%), with most being internal microdeletions. Unexpectedly, the microdeletions did not result in loss of their gene products. Screening PDE4D expression in 11 different types of primary tumor samples (n = 165) with immunohistochemistry staining revealed that its protein levels were up-regulated compared with corresponding nontransformed tissues. Importantly, depletion of endogenous PDE4D with three independent shRNAs caused apoptosis and growth inhibition in multiple types of cancer cells, including breast, lung, ovary, endometrium, gastric, and melanoma, which could be rescued by reexpression of PDE4D. We further showed that antitumor events triggered by PDE4D suppression were lineage-dependently associated with Bcl-2 interacting mediator of cell death (BIM) induction and microphthalmia-associated transcription factor (MITF) downregulation. Furthermore, ectopic expression of the PDE4D short isoform, PDE4D2, enhanced the proliferation of cancer cells both in vitro and in vivo. Moreover, treatmentofcancer cells withaunique specific PDE4D inhibitor, 26B, triggered massive cell death and growth retardation. Notably, these antineoplastic effects induced by either shRNAs or small molecule occurred preferentially in cancer cells but not in nonmalignant epithelial cells. These results suggest that although targeted by genomic homozygous microdeletions, PDE4D functions as a tumor-promoting factor and represents a unique targetable enzyme of cancer cells.Publication MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma(SPRINGERNATURE, 2021-02-09) Ke, Xin-Yu; Chen, Ye; Tham, Valarie Yu-Yan; Lin, Ruby Yu-Tong; Dakle, Pushkar; Nacro, Kassoum; Puhaindran, Mark Edward; Houghton, Peter; Pang, Angela; Lee, Victor Kwanmin; Ding, Ling-Wen; Gery, Sigal; Hill, Jeffrey; Chen, Leilei; Xu, Liang; Koeffler, H Phillip; Assoc Prof Kwan Min Victor Lee; CANCER SCIENCE INSTITUTE OF SINGAPORE; PATHOLOGYSoft tissue sarcoma (STS) is a heterogeneous disease that arises from connective tissues. Clinical outcome of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remains unsatisfactory, despite intensive treatment regimens including maximal surgical resection, radiation, and chemotherapy. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) have been shown to contribute to oncogenic translation via phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). However, little is known about the role of MNK1/2 and their downstream targets in STS. In this study, we show that depletion of either MNK1 or MNK2 suppresses cell viability, anchorage-independent growth, and tumorigenicity of STS cells. We also identify a compelling antiproliferative efficacy of a novel, selective MNK inhibitor ETC-168. Cellular responsiveness of STS cells to ETC-168 correlates positively with that of phosphorylated ribosomal protein S6 (RPS6). Mirroring MNK1/2 silencing, ETC-168 treatment strongly blocks eIF4E phosphorylation and represses expression of sarcoma-driving onco-proteins including E2F1, FOXM1, and WEE1. Moreover, combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells. In summary, our study reveals crucial roles of MNK1/2 and their downstream targets in STS tumorigenesis. Our data encourage further clinical translation of MNK inhibitors for STS treatment.Publication Functional genome-wide screening identifies targets and pathways sensitizing pancreatic cancer cells to dasatinib(Ivyspring International Publisher, 2018) Chien W.; Sudo M.; Ding L.-W.; Sun Q.-Y.; Wuensche P.; Lee K.L.; Hattori N.; Garg M.; Xu L.; Zheng Y.; Gery S.; Wongphayak S.; Yang H.; Baloglu E.; Shacham S.; Kauffman M.; Mori S.; Phillip Koeffler H.; CANCER SCIENCE INSTITUTE OF SINGAPORE; DUKE-NUS MEDICAL SCHOOLThis study is an unbiased genomic screen to obtain functional targets for increased effectiveness of dasatinib in pancreatic cancer. Dasatinib, a multi-targeted tyrosine kinase inhibitor, is used in clinical trials for treatment of pancreatic cancer; however, intrinsic and acquired resistance often occurs. We used a dasatinib-resistant pancreatic cancer cell line SU8686 to screen for synthetic lethality that synergizes with dasatinib using a pooled human shRNA library followed by next generation sequencing. Novel genes were identified which when silenced produced a prominent inhibitory effect with dasatinib against the pancreatic cancer cells. Several of these genes are involved in the regulation of epigenetics, as well as signaling pathways of the FOXO and hedgehog families. Small molecule inhibitors of either histone deacetylases or nuclear exporter had marked inhibitory effect with dasatinib in pancreatic cancers, suggesting their potential therapeutic effectiveness in this deadly cancer. � Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) licensePublication SOX7 is down-regulated in lung cancer(2013) Hayano, T.; Garg, M.; Yin, D.; Sudo, M.; Kawamata, N.; Shi, S.; Chien, W.; Ding, L.-W.; Leong, G.; Mori, S.; Xie, D.; Tan, P.; Koeffler, H.P.; DUKE-NUS GRADUATE MEDICAL SCHOOL S'PORE; CANCER SCIENCE INSTITUTE OF SINGAPOREBackground: SOX7 is a transcription factor belonging to the SOX family. Its role in lung cancer is unknown. Methods. In this study, whole genomic copy number analysis was performed on a series of non-small cell lung cancer (NSCLC) cell lines and samples from individuals with epidermal growth factor receptor (EGFR) mutations using a SNP-Chip platform. SOX7 was measured in NSCLC samples and cell lines, and forced expressed in one of these lines. Results: A notable surprise was that the numerous copy number (CN) changes observed in samples of Asian, non-smoking EGFR mutant NSCLC were nearly the same as those CN alterations seen in a large collection of NSCLC from The Cancer Genome Atlas which is presumably composed of predominantly Caucasians who often smoked. However, four regions had CN changes fairly unique to the Asian EGFR mutant group. We also examined CN changes in NSCLC lines. The SOX7 gene was homozygously deleted in one (HCC2935) of 10 NSCLC cell lines and heterozygously deleted in two other NSCLC lines. Expression of SOX7 was significantly downregulated in NSCLC cell lines (8/10, 80%) and a large collection of NSCLC samples compared to matched normal lung (57/62, 92%, p= 0.0006). Forced-expression of SOX7 in NSCLC cell lines markedly reduced their cell growth and enhanced their apoptosis. Conclusion: These data suggest that SOX7 is a novel tumor suppressor gene silenced in the majority of NSCLC samples. © 2013 Hayano et al.; licensee BioMed Central Ltd.Publication Mutational and transcriptomic profiling of acute leukemia of ambiguous lineage reveals obscure but clinically important lineage bias(Ferrata Storti Foundation (Haematologica), 2019-05-01) Lao, ZT; Ding, LW; An, O; Hattori, N; Sun, QY; Tan, KT; Mayakonda, A; Chuan, WG; Madan, V; Lin, DC; Yang, H; Koeffler, HP; Dr Omer An; MEDICINE; CANCER SCIENCE INSTITUTE OF SINGAPOREAcute leukemia of ambiguous lineage (ALAL) is a rare group of blood cancers that cannot be clearly classified into either myeloid or lymphoid lineage through traditional immunophenotyping (2016 World Health Organization classification). In this study, we performed exome and transcriptome sequencing of 15 diagnosis/relapse samples to identify mutations of this disease. Remarkably, genes involved in DNA repair pathway were frequently mutated and occurred in 80% of the samples. In addition, well known mutations of hematopoietic neoplasms were found in these samples, such as DNMT3A, RUNX1, NOTCH1 and NRAS. A number of ALAL samples simultaneously harboured mutations of both myeloid and lymphoid neoplasm associated genes, which may explain (at least partially) the mixed lineage phenotype of this abnormality. Our study provides novel insights into this rare leukemic entity which may help to develop a better therapeutic strategy. Copyright © 2018, Ferrata Storti Foundation.
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