生物醫學研究所

研究方向及研究室特色

(一)探討大腸癌細胞在缺氧環境下的轉譯調控

大腸癌是人類很普遍的癌症，在國人癌症死因中排名第三(僅次於肺癌及肝癌)，其發生率在最近這幾年仍持續穩定增加，雖然已經有研究報告讓我們了解大腸癌形成的基因突變過程，然而許多大腸癌末期病人卻常因為治療無效而死亡，其五年存活率仍舊不高，因此我們需要有新的策略及療法來治療大腸癌。

細胞缺氧是普遍常見的生理及病理現象，以腫瘤生成為例，由於癌細胞的快速增生及異常的血管新生造成腫瘤內有許多不同程度的缺氧區域，癌細胞可藉由改變基因表現來適應缺氧的壓力，缺氧在腫瘤惡化過程中也扮演重要的角色，腫瘤內的缺氧細胞也是造成臨床預後不良的重要原因，已有研究顯示經過缺氧處理的癌細胞對於放射治療及化學治療有較強的抵抗能力，因此，深入了解缺氧所導致的基因表現及調控，可能開啟未來在癌症治療上的新契機。

     我們目前的研究方向如下：

(1)  了解大腸癌細胞在缺氧環境下基因表現的改變。

(2)  研究大腸癌細胞在缺氧環境下進行轉譯調控的分子機制。

(3)  找尋大腸癌臨床診斷的生物標記及抗癌標的。

(二)研究DEAD-box RNA解旋酶DDX3的生物功能

    人類DDX3蛋白是DEAD-box RNA解旋酶的家族成員之一，這類RNA解旋酶在真核生物的基因表現上扮演不可或缺的角色，DDX3及其同源蛋白已被證明參與mRNA代謝的許多過程，包括蛋白質轉譯。我們之前的研究發現：細胞在壓力環境下，DDX3會集中到細胞質的壓力體(SGs)中，暗示DDX3在轉譯初期上扮演角色。DDX3對於一般mRNA的轉譯並非必要，但可協助具有較長及二級結構5' UTR的特定mRNA轉譯。考量DDX3在執行轉譯功能時需要其RNA解旋酶活性，因此我們認為DDX3在轉譯初期可能藉由解開特定mRNA的5' UTR二級結構來協助核糖體掃描。

    我們目前的研究方向如下：

(1)  探討DDX3對於microRNA生合成的重要性。

(2)  研究DDX3在生殖細胞發育中所扮演的角色。

(3)  DDX3的後轉譯修飾對其功能的影響及調控。

最近五年所發表論文

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)

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.