A. Characterization of translational regulation during hypoxia in human colon cancer cells
Colon cancer, also called colorectal cancer (CRC), is one of the most common cancers in the world. In Taiwan, CRC has risen to the third leading cause of all cancer deaths. The incidence of CRC has been rising steadily in the last 20 years. Although studies of CRC have provided valuable insights into the multistep genetic process of carcinogenesis, many patients with invasive/metastatic CRC still die within five years due to treatment failure. Thus, new strategies and better therapeutics are still required for the therapy of CRC.
Hypoxia occurs in a wide variety of physiological and pathological conditions, including tumorigenesis. Because of rapid proliferation and aberrant angiogenesis, tumors contain areas with various degrees of hypoxia. Tumor cells have to adapt to hypoxia by altering their gene expression. Hypoxia plays a key role in tumor progression and malignancy. Importantly, the presence of hypoxic cells in solid tumors is associated with poor prognosis. Previous studies have shown that hypoxic tumor cells are more resistant to radiotherapy and many commonly used chemotherapeutic agents. A better understanding of hypoxia-induced gene expression changes may open perspectives for future tumor therapy.
Our current work is focused on the following issues and interests.
(a) Identification of hypoxia-regulated genes at the translational level in human colon cancer cells
(b) Molecular mechanisms of hypoxia-induced translational regulation in human colon cancer cells
(c) Identification of IRES trans-acting factors (ITAFs) which activate IRES-mediated translation during hypoxia
(d) To search for diagnostic biomarkers and anti-cancer targets of human colon cancer
B. Functional study of DEAD-box RNA helicase DDX3
Human DDX3 is a member of the DEAD-box RNA helicases that play important roles in eukaryotic gene expression. DDX3 and its homologs have been implicated in many aspects of mRNA metabolism, including translation initiation. We have previously reported that DDX3 is recruited to cytoplasmic stress granules (SGs) under cell stress conditions, suggesting a role for DDX3 in translation. DDX3 is dispensable for translation of general mRNAs, but it can facilitate translation of selected mRNAs that contain a long or structured 5’ untranslated region (UTR). Given that the RNA helicase activity of DDX3 is required for its function in translation, we suggested that DDX3 may facilitate ribosome scanning by resolving secondary structures in the 5’ UTR of selected mRNAs during translation initiation.
It would be interesting to investigate the biological functions of DDX3-mediated translational control. There are still many unanswered questions as follows:
(a) Translational control of DDX3 in innate immunity.
(b) Translational control of DDX3 in microRNA maturation.
(c) Translational control of DDX3 in germline development.
(d) Functional studies of post-translational modification of DDX3.
- Tsung-Ming Chen, Ming-Chih Lai, Yi-Han Li, Ya-Ling Chan, Chih-Hao Wu, Yu-Ming Wang, Chun-Wei Chien, San-Yuan Huang, H. Sunny Sun*, Shaw-Jenq Tsai*. (2019). hnRNPM induces translation switch under hypoxia to promote colon cancer development. EBioMedicine doi: 10.1016/j.ebiom.2019.02.059 (SCI, 2017 IF=6.183, Ranking 13/133 in MEDICINE, RESEARCH & EXPERIMENTAL)
- Yu-Chang Ku, Min-Hua Lai, Chen-Chia Lo, Yi-Chuan Cheng, Jian-Tai Qiu, Woan-Yuh Tarn, Ming-Chih Lai*. (2019). DDX3 participates in translational control of inflammation induced by infections and injuries. Mol. Cell. Biol. 39(1): e00285-18 (SCI, 2017 IF=3.813, Ranking 85/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Jeng-Ting Chen, Chien-Chun Liu, Jau-Song Yu, Hung-Hsuan Li, Ming-Chih Lai*. (2018). Integrated omics profiling identifies hypoxia-regulated genes in HCT116 colon cancer cells. J. Proteomics 188: 139-151 (SCI, 2017 IF=3.722, Ranking 17/79 in BIOCHEMICAL RESEARCH METHODS)
- Ming-Chih Lai*, Chiao-May Chang, H. Sunny Sun*. (2016). Hypoxia induces autophagy through translational up-regulation of lysosomal proteins in human colon cancer cells. PLOS ONE 11(4): e0153627 (SCI, 2017 IF=2.766, Ranking 15/64 in MULTIDISCIPLINARY SCIENCES)
- Ming-Chih Lai*, H. Sunny Sun, Shainn-Wei Wang, Woan-Yuh Tarn*. (2016). DDX3 functions in antiviral innate immunity through translational control of PACT.
FEBS J. 283(1): 88-101 (SCI, 2017 IF=4.530, Ranking 58/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Tsung-Ming Chen, Yu-Heng Shih, Joseph T. Tseng, Ming-Chih Lai, Chih-Hao Wu, Yi-Han Li, Shaw-Jenq Tsai*, H. Sunny Sun*. (2014). Overexpression of FGF9 in colon cancer cells is mediated by hypoxia-induced translational activation. Nucleic Acids Res. 42(5): 2932-2944 (SCI, 2017 IF=11.561, Ranking 10/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Ming-Chih Lai, Shainn-Wei Wang, Lie Cheng, Woan-Yuh Tarn, Shaw-Jenq Tsai*, H. Sunny Sun*. (2013). Human DDX3 interacts with the HIV-1 Tat protein to facilitate viral mRNA translation. PLOS ONE 8(7): e68665 (SCI, 2017 IF=2.766, Ranking 15/64 in MULTIDISCIPLINARY SCIENCES)
- Woan-Yuh Tarn*, Ming-Chih Lai*. (2011). Translational control of cyclins. Cell Div. 6(1):5 (SCI, 2017 IF=4.684, Ranking 57/190 in CELL BIOLOGY)
- Ming-Chih Lai, Wen-Cheng Chang, Sheau-Yann Shieh, Woan-Yuh Tarn*. (2010). DDX3 regulates cell growth through translational control of cyclin E1.
Mol. Cell. Biol. 30(22): 5444-5453 (SCI, 2017 IF=3.813, Ranking 85/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Ming-Chih Lai, Tsui-Yi Peng, Woan-Yuh Tarn*. (2009). Functional interplay between viral and cellular SR proteins in control of post-transcriptional gene regulation. FEBS J. 276(6): 1517-1526 (SCI, 2017 IF=4.530, Ranking 58/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Ming-Chih Lai, Yan-Hwa Wu Lee, Woan-Yuh Tarn*. (2008). The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control. Mol. Biol. Cell 19(9): 3847-3858 (SCI, 2017 IF=3.512, Ranking 87/190 in CELL BIOLOGY)
- Ming-Chih Lai, Woan-Yuh Tarn*. (2004). Hypophosphorylated ASF/SF2 binds TAP and is present in messenger ribonucleoproteins. J. Biol. Chem. 279: 31745- 31749 (SCI, 2017 IF=4.010, Ranking 75/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Ming-Chih Lai, Hao-Wei Kuo, Wen-Cheng Chang, Woan-Yuh Tarn*. (2003). A novel splicing regulator shares a nuclear import pathway with SR proteins.
EMBO J. 22(6): 1359-1369 (SCI, 2017 IF=10.557, Ranking 13/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Chin Li, Ru-Inn Lin, Ming-Chih Lai, Pin Ouyang, Woan-Yuh Tarn*. (2003). Nuclear Pnn/DRS protein binds to spliced mRNPs and participates in mRNA processing and export via interaction with RNPS1. Mol. Cell. Biol. 23(20): 7363-7376 (SCI, 2017 IF=3.813, Ranking 85/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Ming-Chih Lai, Ru-Inn Lin, Woan-Yuh Tarn*. (2003). Differential effects of hyperphosphorylation on splicing factor SRp55. Biochem. J. 371(Pt 3): 937-945 (SCI, 2017 IF=3.857, Ranking 81/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Ming-Chih Lai, Ru-Inn Lin, Woan-Yuh Tarn*. (2001). Transportin-SR2 mediates nuclear import of phosphorylated SR proteins. Proc. Natl. Acad. Sci. USA 98(18): 10154-10159 (SCI, 2017 IF=9.504, Ranking 5/64 in MULTIDISCIPLINARY SCIENCES)
- Ming-Chih Lai, Ru-Inn Lin, Shin-Yi Huang, Ching-Wei Tsai, Woan-Yuh Tarn*. (2000). A human importin-β family protein, transportin-SR2, interacts with the phosphorylated RS domain of SR proteins. J. Biol. Chem. 257(11): 7950-7957 (SCI, 2017 IF=4.010, Ranking 75/292 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Ming-Chih Lai, Bee Heong Teh, Woan-Yuh Tarn*. (1999). A human papillomavirus E2 transcriptional activator. The interactions with cellular splicing factors and potential function in pre-mRNA processing. J. Biol. Chem. 274(17): 11832-11841 (SCI, 2017 IF=4.010, Ranking 75/293 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
- Ming-Chih Lai, Yuung-Chiarng Wang, Feng-Yuan Yang, Lo-Chun Au*. (1997). Enhancement of transfection efficiency by using oligodeoxyribonucleotide as carrier. Anal. Biochem. 251(2): 292-294 (SCI, 2017 IF=2.275, Ranking 42/79 in BIOCHEMICAL RESEARCH METHODS)