91猫先生

研究方向及研究室特色

(一)探讨大肠癌细胞在缺氧环境下的转译调控

大肠癌是人类很普遍的癌症，在国人癌症死因中排名第叁(仅次於肺癌及肝癌)，其发生率在最近这几年仍持续稳定增加，虽然已经有研究报告让我们了解大肠癌形成的基因突变过程，然而许多大肠癌末期病人却常因為治疗无效而死亡，其五年存活率仍旧不高，因此我们需要有新的策略及疗法来治疗大肠癌。

细胞缺氧是普遍常见的生理及病理现象，以肿瘤生成為例，由於癌细胞的快速增生及异常的血管新生造成肿瘤内有许多不同程度的缺氧区域，癌细胞可藉由改变基因表现来适应缺氧的压力，缺氧在肿瘤恶化过程中也扮演重要的角色，肿瘤内的缺氧细胞也是造成临床预后不良的重要原因，已有研究显示经过缺氧处理的癌细胞对於放射治疗及化学治疗有较强的抵抗能力，因此，深入了解缺氧所导致的基因表现及调控，可能开啟未来在癌症治疗上的新契机。

     我们目前的研究方向如下：

(1)  了解大肠癌细胞在缺氧环境下基因表现的改变。

(2)  研究大肠癌细胞在缺氧环境下进行转译调控的分子机制。

(3)  找寻大肠癌临床诊断的生物标记及抗癌标的。

(二)研究DEAD-box RNA解旋酶DDX3的生物功能

    人类DDX3蛋白是DEAD-box RNA解旋酶的家族成员之一，这类RNA解旋酶在真核生物的基因表现上扮演不可或缺的角色，DDX3及其同源蛋白已被证明参与mRNA代谢的许多过程，包括蛋白质转译。我们之前的研究发现：细胞在压力环境下，DDX3会集中到细胞质的压力体(SGs)中，暗示DDX3在转译初期上扮演角色。DDX3对於一般mRNA的转译并非必要，但可协助具有较长及二级结构5' UTR的特定mRNA转译。考量DDX3在执行转译功能时需要其RNA解旋酶活性，因此我们认為DDX3在转译初期可能藉由解开特定mRNA的5' UTR二级结构来协助核糖体扫描。

    我们目前的研究方向如下：

(1)  探讨DDX3对於microRNA生合成的重要性。

(2)  研究DDX3在生殖细胞发育中所扮演的角色。

(3)  DDX3的后转译修饰对其功能的影响及调控。

最近五年所发表论文

1.   Hung-Hsuan Li, Hsin-Yuan Hung, Jau-Song Yu, Ming-Chih Lai*. (2024 Dec). Hypoxia-induced translation of collagen-modifying enzymes PLOD2 and P4HA1 is dependent on RBM4 and eIF4E2 in human colon cancer HCT116 cells. FEBS J. (SCI, 2023 IF= 5.5, Ranking 58/313 in BIOCHEMISTRY & MOLECULAR BIOLOGY)

2.     Shang-Yu Tsai, Chih-Hung Lin, Yu-Ting Jiang, Guo-Jen Huang, Haiwei Pi, Hsin-Yuan Hung, Woan-Yuh Tarn, Ming-Chih Lai*. (2024 Nov). DDX3 is critical for female fertility via translational control in oogenesis. Cell Death Discovery 10(1):472. (SCI, 2023 IF= 6.1, Ranking 49/205 in CELL BIOLOGY)

3.     Ming-Chih Lai^*, Yen-Ling Yu, Chiao-Nung Chen, Jau-Song Yu, Hsin-Yuan Hung, Shih-Peng Chan^*. (2024 Nov). DDX3 participates in miRNA biogenesis and RNA interference through translational control of PACT and interaction with AGO2. FEBS Open Bio doi: 10.1002/2211-5463.13920. (SCI, 2023 IF= 2.8, Ranking 184/313 in BIOCHEMISTRY & MOLECULAR BIOLOGY)

4.     Ming-Chih Lai*, Yi-Pin Chen, Ding-An Li, Jau-Song Yu, Hsin-Yuan Hung, Woan-Yuh Tarn* (2022 Feb) DDX3 interacts with USP9X and participates in deubiquitination of the anti-apoptotic protein MCL1. FEBS J. 289(4): 1043-1061. (SCI, 2023 IF= 5.5, Ranking 58/313 in BIOCHEMISTRY & MOLECULAR BIOLOGY)

5.     Ming-Chih Lai, Han-Hsiang Chen, Peng Xu, Robert YL Wang*. (2020 Jan). Translation control of Enterovirus A71 gene expression. Journal of Biomedical Science 27(1):22. (SCI, 2023 IF= 9.0 Ranking 30/205 in CELL BIOLOGY)

6.     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 Mar). hnRNPM induces translation switch under hypoxia to promote colon cancer development. EBioMedicine 41: 299-309. (SCI, 2023 IF= 9.7, Ranking 12/189 in MEDICINE, RESEARCH & EXPERIMENTAL)

7.     Yu-Chang Ku, Min-Hua Lai, Chen-Chia Lo, Yi-Chuan Cheng, Jian-Tai Qiu, Woan-Yuh Tarn, Ming-Chih Lai*. (2018 Dec). DDX3 participates in translational control of inflammation induced by infections and injuries. Mol. Cell. Biol. 39(1): e00285-18. (SCI, 2023 IF= 3.2, Ranking 155/313 in BIOCHEMISTRY & MOLECULAR BIOLOGY)

8.     Jeng-Ting Chen, Chien-Chun Liu, Jau-Song Yu, Hung-Hsuan Li, Ming-Chih Lai*. (2018 Sep). Integrated omics profiling identifies hypoxia-regulated genes in HCT116 colon cancer cells. J. Proteomics 188: 139-151. (SCI, 2023 IF= 2.8, Ranking 35/85 in BIOCHEMICAL RESEARCH METHODS)

9.     Ming-Chih Lai*, Chiao-May Chang, H. Sunny Sun*. (2016 Apr). Hypoxia induces autophagy through translational up-regulation of lysosomal proteins in human colon cancer cells. PLOS ONE 11(4): e0153627. (SCI, 2023 IF= 2.9, Ranking 31/134 in MULTIDISCIPLINARY SCIENCES)

10.  Ming-Chih Lai*, H. Sunny Sun, Shainn-Wei Wang, Woan-Yuh Tarn*. (2016 Jan). DDX3 functions in antiviral innate immunity through translational control of PACT. FEBS J. 283(1): 88-101. (SCI, 2023 IF= 5.5, Ranking 58/313 in BIOCHEMISTRY & MOLECULAR BIOLOGY)

11.  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 Mar). Overexpression of FGF9 in colon cancer cells is mediated by hypoxia-induced translational activation. Nucleic Acids Res. 42(5): 2932-2944. (SCI, 2023 IF= 16.6, Ranking 6/313 in BIOCHEMISTRY & MOLECULAR BIOLOGY)

Lab & Research Interest

A. Functional study of DEAD-box RNA helicase DDX3

DEAD-box RNA helicases play essential roles in almost all aspects of mRNA metabolism, including ribosome biogenesis, transcription, RNA processing, RNA export, translation, and RNA decay. Previously, we demonstrated that DDX3 is crucial for the translation of selected mRNAs that have long or structured 5’ untranslated regions (UTRs). Since the RNA helicase activity of DDX3 is necessary for its function in translation, we proposed 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. However, several questions remain unanswered, including:

(a) The role of DDX3 in miRNA biogenesis and RNA interference

(b) The importance of DDX3 in oogenesis and female fertility

(c) The impact of DDX3 on neuronal development

(d) The involvement of DDX3 in neurodegenerative diseases

B. The mechanisms of hypoxia-induced translation in human colon cancer cells

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. In Taiwan, CRC has ranked first in cancer incidence for the past 15 years. Many patients with invasive or metastatic CRC die within five years due to treatment failure. Therefore, new strategies and improved therapeutics are required for CRC treatment. Hypoxia, a condition characterized by low oxygen levels, occurs in various physiological and pathological conditions, including tumor development. Tumor hypoxia significantly contributes to tumor progression and is associated with a poor prognosis. A better understanding of how hypoxia induces changes in gene expression may open up new prospects for future cancer treatments. Our current research focuses on the following issues:

(a) Characterizing the molecular mechanisms behind hypoxia-induced translation in human colon cancer cells

(b) Identifying RNA-binding proteins that activate the translation of specific mRNAs under hypoxic conditions

(c) Searching for diagnostic biomarkers and potential anti-cancer targets for CRC

C. To improve recombinant protein productivity in Chinese hamster ovary cells

It is important to note that nearly 80% of approved human therapeutic antibodies are produced by Chinese hamster ovary (CHO) cells. In order to increase the production of recombinant proteins and reduce cell culture costs, we plan to utilize genetic engineering techniques to improve CHO cell lines.