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Liang-Chuan Lai, Ph.D.
Professor,
Graduate Institute of Physiology,
National Taiwan University College of Medicine
Taipei, Taiwan

TEL: 886-(02)23123456 ext. 88241
FAX: 886-(02)23938235
E-mail: llai@ntu.edu.tw

Academic Hub

ORCID ID: 0000-0002-3913-5338

ResearcherID: B-4768-2009

Scopus Author ID: 720261626

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Lab topic
Our major research interests are using microarray or next generation sequencing to explore the cancer genomics. Approaches to understand the mechanism of cancer genome by investigating gene expression profiling, copy number variation, single nucleotide polymorphism, epigenetics and microRNA in several cancers, including lung cancer, breast cancer, and esophageal cancer.
Recently we identified that several semaphorin gene family members can be used as potential therapeutic targets, and that SEMA5A may be useful as a prognostic biomarker for non-smoking women with non-small cell lung carcinoma.

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Research topic
Investigation of regulatory mechanism of NDRG1 upon reoxygenatio
Hypoxia has been intensively investigated over the past decades based on the observations that hypoxic tumors were more resistant to therapy and had a worse prognosis. However, the oxygen concentration within hypoxic tumors was highly variable, because tumor vasculature was both inefficient and unstable. The hypoxic regions could become rapidly re-perfused or re-oxygenated. Several studies have been reported that tumor cells displayed increases in drug resistance and metastatic potential after exposed to hypoxia/reoxygenation insults. Therefore, it is necessary to consider hypoxia and reoxygenation as two parts of the same stress response as they were inevitably associated with each other. Although cellular adaptation to hypoxia was well documented, little was known about adaptive mechanisms to reoxygenation.
In our previous genomic study on breast cancer cells upon reoxygenation, we identified 127 genes involved in this response. Pathway analysis revealed that these oxygen-responsive genes were enriched in HIF-1-alpha transcription factor network, and validated targets of C-MYC transcriptional activation. Among these differentially expressed genes upon reoxygenation, NDRG1 had the maximal response and was regulated by MYC signalling pathway. Therefore, we hypothesize that NDRG1 may play an important role in tumor adaptation to fluctuation of oxygen concentrations. Although several studies suggested that NDRG1 is induced by hypoxia and associated with metastasis, the regulatory mechanism of NDRG1 remains elusive and its function under reoxygenation is still unclear. Hence, we propose to comprehensively investigate the regulatory mechanism of NDRG1 upon changes in oxygen concentrations. In order to prove our hypothesis, we propose to conduct experiments with the following specific aims:

1. Identification of transcription factors that directly regulate NDRG1 and their binding sites;
2. Identification of microRNAs that directly regulate NDRG1 and their binding sites;
3. Investigation of methylation status in the promoter of NDRG1 regulating its expression;
4. Investigation of functional roles of NDRG1 using in vitro and in vivo assays.

Using genetic approaches, functional assays, and in silico analysis, this study will allow us to get a deep insight of the genetic mechanisms and functional roles of NDRG1 upon oxygen variation in transformed cells. By a better understanding of the molecular mechanism that cancer cells adapt to the tumor microenvironment, we hope to contribute in developing a more specific therapeutic regime to treat cancer.

Regulation of transcription and metastasis of semaphorin family in lung cancer
Lung cancer is the leading cause of cancer death in Taiwan. The increase of lung cancer mortality rate in Taiwan has become the highest in the world. Despite advances in early detection and standard treatment, lung cancer is still often diagnosed at an advanced stage and has a poor prognosis, with less than 15% of overall 5-year survival rate. Although smoking is the major risk factor for lung cancer, only < 20% smokers have lung cancer. Furthermore, transforming normal bronchial epithelial cells to lung cancer requires a number of genetic molecular lesions. Although several genes, such as EGFR, KRAS, PI3K, p53, etc., have been reported to be involved in lung tumorigenesis, the detail mechanisms still remain unclear. In our previous genomic study on non-smoking female lung cancer patients, we identified that several genes in semaphorin (SEMA) family (e.g. SEMA3B, SEMA3G, SEMA5A, SEMA6A, and SEMA6D) were very significantly down-regulated. Functional analysis also revealed that genes involved in axonal guidance signaling and Ephrin receptor signaling were in the top three enriched functional categories. However, little is known about the role of SEMA genes in the lung cancer. Because these guidance molecules act in general to regulate cell migration and adhesion, we hypothesize that they are involved in mechanisms of disease progression in lung carcinogenesis. In order to prove our hypothesis, we propose to conduct experiments with the following specific aims:

1. To investigate the effect of semaphorin genes in lung carcinogenesis by over-expressing SEMA genes in human lung cancer cells;
2. To understand the molecular mechanisms of semaphorin genes in lung carcinogenesis by microarray analysis;
3. To further characterize the functional roles of semaphorin genes in athymus nude mouse model.

Using genetic approach, functional assays, and microarray analysis, this study will allow us to get an insight of the functional roles and genetic mechanisms of semaphorin gene family in lung cancer. By a better understanding of the molecular origins and evolution of the disease, we hope to contribute in developing a more specific therapeutic regime to treat lung cancer.

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