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Research highlights of Laboratory of Cancer Drug Discovery
Our laboratory is interested in identifying new biomarkers using public databases, such as The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), for predicting the effectiveness of anti-cancer therapies, e.g. radiotherpy, chemotherapy and immunotherapy, in different cancer types. We have set up several cell-based assays to examine the irradiation/chemotherapeutic/immunotherapeutic sensitivity and cellularl migration/invasion ability of tested cancer cells. We have also established orthotopic mouse models for brest cancer and oral cancer to evaluate the capacity of identified oncogenic drivers in promoting tumor growth and distant metastasis. Because genetic defects frequently result in the alteration of protein-protein interaction (PPI) network, our laboratory is also interested in discovering drug-targetable PPIs in malignancies by utiziling iodoacetamide-based probes.
Email | td001089012@tmu.edu.tw
Profile | Academic Hub/Pure Experts
Lin, Yuan-Feng
Lin, Yuan-Feng
Graduate Institute of Clinical Medicine
Professor
Research Interests
Cell and Molecular Biology, Cancer Biology, Cancer Stem Cells, Cancer Molecular Medicine, Pancreatic Cancer, Breast Cancer, Cancer Treatment Resistance
Laboratory
Laboratory of Cancer Drug Discovery
Prof. Lin received his Ph.D degree from Taipei Medical University, Taiwan, in 2007 and completed his postdoctoral training at Institute of Biological Chemistry, Academia Sinica, Taiwan , in 2014. As postdoctoral fellow, Prof. Lin worked on screening of protein targets using iodoacetamined-based probes for developing new anti-cancer drugs and identified that targeting the protein-protein interactions (PPIs) of CCT-beta/beta-tubulin (Cancer Research, 2009) and XIAP/Caspase-7 (Journal of Clinical Investigation, 2013) complexes are capable of effectively killing multidrug-resistant cancers. Then, Prof. Lin was employed as Assitance Professor in 2014 and became the Full Professor in 2021 at Graduate Institute of Clinical Medicine, Taipei Medical University.
01
Shang-Pen Huang
M.D. , Ph.D. (Co-investigator in GBM)
02
Hui-Yu Lin
M.D. , Ph.D. (Co-investigator in Breast Cancer)
03
Chia-Hao Kuei
M.D. , Ph.D. (Co-investigator in Prostate Cancer)
04
Che-Hsuan Lin
M.D. , Ph.D. (Co-investigator in Oral Cancer)
05
Hsun-Hua Lee
M.D. , Ph.D. (Co-investigator in GBM)
06
Kung-Ju Chen
Ph.D. (Postdoctral Fellow)
07
Jing-Quan Zheng
M.D. (PhD student focusing on Lung Cancer)
08
Wen-Ke Wang
M.D. (PhD student focusing on Breast Cancer)
09
Yang-Sheng Lin
M.D. (PhD student focusing on Colorectal Cancer)
10
Yiu-Shun Tong
M.D. (PhD student focusing on Colorectal Cancer)
11
Leon Tsung-Ju Lee
M.D. (PhD student focusing on Melanoma)
12
Kevin Shu Leung Lai
M.D. (PhD student focusing on Lung Cancer)
13
Hsiao-Wei Lu
M.D. (PhD student focusing on Oral Cancer)
14
Ruei-Chen Hun
M.S. (PhD student focusing on Breast Cancer)
15
Salman Mohamed Farah
M.S. (PhD student focusing on Breast Cancer)
2023
Yuan TZ, Lin HY, Kuei CH, Lin CH, Lee HH, Lee HL, Lu HW, Su CY, Chiu HW, Lin YF*.
NEDD8 promotes radioresistance via triggering autophagy formation and serves as a novel prognostic marker in oral squamous cell carcinoma.
Cancer Cell Int. 2023 Mar 8;23(1):41.
Abstract
Neddylation is a post-translational protein modification process. MLN4924 is a newly discovered pharmaceutical neddylation inhibitor that suppresses cancer growth with several cancer types. In our study, we first investigated the effect of MLN4924 on colon cancer cells (HCT116 and HT29). MLN4924 significantly inhibited the neddylation of cullin-1 and colon cancer cell growth in a time and dose-depen-dent manner. MLN4924 induced G2/M cell cycle arrest and apoptosis in HCT116 and HT29 cells. Moreover, MLN4924 also triggered autophagy in HCT116 and HT29 cells via suppressing the PI3K/AKT/mTOR pathway. Inhibiting autophagy by autophagy inhibitor 3-MA or ATG5 knockdown reversed the function of MLN4924 in suppress-ing colon cancer cell growth and cell death. Interestingly, MLN4924 suppresses colon cell growth in a xenograft model. Together, our finding revealed that blocking ned-dylation is an attractive colon cancer therapy strategy, and autophagy might act as a novel anti-cancer mechanism for the treatment of colon cancer by MLN4924.
Zheng JQ, Lin CH, Lee HH, Chang WM, Li LJ, Su CY, Lee KY, Chiu HW, Lin YF*.
AIM2 upregulation promotes metastatic progression and PD-L1 expression in lung adenocarcinoma.
Cancer Sci. 2023 Jan;114(1):306-320.
Abstract
Cancer metastasis leading to the dysfunction of invaded organs is the main cause of the reduced survival rates in lung cancer patients. However, the molecular mechanism for lung cancer metastasis remains unclear. Recently, the increased activity of inflammasome appeared to correlate with the metastatic progression and immunosuppressive ability of various cancer types. Our results showed that the mRNA levels of absence in melanoma 2 (AIM2), one of the inflammasome members, are extensively upregulated in primary tumors compared with normal tissues derived from the TCGA lung adenocarcinoma (LUAD) database. Moreover, Kaplan‐Meier analysis demonstrated that a higher mRNA level of AIM2 refers to a poor prognosis in LUAD patients. Particularly, AIM2 upregulation is closely correlated with smoking history and the absence of EGFR/KRAS/ALK mutations in LUAD. We further showed that the endogenous mRNA levels of AIM2 are causally associated with the metastatic potentials of the tested LUAD cell lines. AIM2 knockdown suppressed but overexpression promoted the migration ability and lung colony–forming ability of tested LUAD cells. In addition, we found that AIM2 upregulation is closely associated with an increased level of immune checkpoint gene set, as well as programmed cell death‐ligand 1 (PD‐L1) transcript, in TCGA LUAD samples. AIM2 knockdown predominantly repressed but overexpression enhanced PD‐L1 expression via altering the activity of PD‐L1 transcriptional regulators NF‐κB/STAT1 in LUAD cells. Our results not only provide a possible mechanism underlying the AIM2‐promoted metastatic progression and immune evasion of LUAD but also offer a new strategy for combating metastatic/immunosuppressive LUAD via targeting AIM2 activity.
2020
Kuei CH, Lin HY, Lin MH, Lee HH, Lin CH, Lee WJ, Chen YL, Lu LS, Zheng JQ, Hung RC, Chiu HW, Chen KC, Lin YF*.
DNA polymerase theta repression enhances the docetaxel responsiveness in metastatic castration-resistant prostate cancer.
Biochim Biophys Acta Mol Basis Dis. 2020 Dec 1;1866(12):165954.
Abstract
Objective: Docetaxel remains a main treatment for metastatic castration-resistant prostate cancer (mCRPC); however, the development of docetaxel resistance has been found in some mCRPC patients. The aim of this work is to identify an effective biomarker for predicting therapeutic effectiveness of docetaxel in mCRPC patients. Methods: We examined DNA polymerase theta (POLQ) expression in The Cancer Genome Atlas (TCGA) database and Tissue microarray. Kaplan-Meier analyses were performed to estimate the prognostic significance of POLQ. A series of functional analyses were conducted in cell lines and xenograft models. Regulated pathways were predicted by Geneset Enrichment Analysis (GSEA) software and further investigated by luciferase reporter and RT-PCR assays. Results: We found that POLQ mRNA levels in CRPC tissues was significantly higher than that of other DNA polymerases in non-CRPC prostate tissues. POLQ upregulation was extensively detected in mCRPC and strongly predicted a poor prognosis. POLQ knockdown enhanced docetaxel sensitivity in a cell-based cytotoxicity assay and promoted the therapeutic effect on the tumor growth of metastatic PC-3M cells in xenograft models. The computational simulation by GSEA software significantly predicted the association between POLQ upregulation and the activation of E2F/G2M checkpoint-related pathways. Moreover, luciferase reporter and RT-PCR assays demonstrated that POLQ knockdown downregulated the transcriptional regulatory activity of E2F and repressed E2F/G2M checkpoint-regulated CDK1 in mCRPC cells. Conclusion: Our results suggest that POLQ serves as a predictive factor for poor docetaxel response and provide a novel strategy to enhance the anticancer effects of docetaxel therapy by targeting POLQ in mCRPC patients.
2019
Lin YF, Chou JL, Chang JS, Chiu IJ, Chiu HW, Lin YF*.
Dysregulation of the miR-25-IMPA2 axis promotes metastatic progression in clear cell renal cell carcinoma.
EBioMedicine. 2019 Jul;45:220-230.
Abstract
2017
Huang SP, Liu PY, Kuo CJ, Chen CL, Lee WJ, Tsai YH, Lin YF*.
The Gαh-PLCδ1 signaling axis drives metastatic progression in triple-negative breast cancer.
J Hematol Oncol. 2017 Jun 2;10(1):114. 3.
Abstract
Background: Distant metastasis of triple-negative breast cancer (TNBC) to other organs, e.g., the lungs, has been correlated with poor survival rates among breast cancer patients. Therefore, the identification of useful therapeutic targets to prevent metastasis or even inhibit tumor growth of TNBC is urgently needed. Gαh is a novel GTP-binding protein and known as an inactive form of calcium-dependent tissue transglutaminase. However, the functional consequences of transamidating and G-protein activities of tissue transglutaminase in promoting cancer metastasis are still controversial. Methods: Kaplan-Meier analyses were performed to estimate the prognostic values of Gαh and PLCδ1 by utilizing public databases and performing immunohistochemical staining experiments. Cell-based invasion assays and in vivo lung colony-forming and orthotropic lung metastasis models were established to evaluate the effectiveness of interrupting the protein-protein interaction (PPI) between Gαh and PLCδ1 in inhibiting the invasive ability and metastatic potential of TNBC cells. Results: Here, we showed that the increased level of cytosolic, not extracellular, Gαh is a poor prognostic marker in breast cancer patients and correlates with the metastatic evolution of TNBC cells. Moreover, clinicopathological analyses revealed that the combined signature of high Gαh/PLCδ1 levels indicates worse prognosis in patients with breast cancer and correlates with lymph node metastasis of ER-negative breast cancer. Blocking the PPI of the Gαh/PLCδ1 complex by synthetically myristoylated PLCδ1 peptide corresponding to the Gαh-binding interface appeared to significantly suppress cellular invasiveness in vitro and inhibit lung metastatic colonies of TNBC cells in vivo. Conclusions: This study establishes Gαh/PLCδ1 as a poor prognostic factor for patients with estrogen receptor-negative breast cancers, including TNBCs, and provides therapeutic value by targeting the PPI of the Gαh/PLCδ1 complex to combat the metastatic progression of TNBCs.
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