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

 

 

  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.

 

 

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:

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.

 

 

Breast cancer is one of the most common cancers each year worldwide. Moreover, microenvironmental hypoxia, a hallmark of solid tumors, is observed in breast cancer cells, because of the rapid growth of tumor cells and inadequate vascular distribution in tumor microenvironment. In order to adapt to a hypoxic environment, tumors activate multiple cellular responses and lead to solid tumor aggressiveness. However, the hypoxic regions could become rapidly re-perfused or re-oxygenated, because tumor vasculature was both inefficient and unstable. Although cellular adaptation to hypoxia was well documented, little was known about adaptive mechanisms to reoxygenation.
Recently, since the advance of high-resolution microarray (i.e., DNA tiling arrays) and genome-wide sequencing technology (i.e., next generation sequencing) is greatly progressive, massive amount of novel transcripts are revealed. It has been estimated that near 70% of the genome is transcribed, but only 2% of the human genome encode proteins. RNA molecules that lack protein coding potential are typically referred to as non-coding RNAs (ncRNAs), which can be divided small ncRNAs (< 200 nt) and long ncRNAs (lncRNA) according to their size.

 

Long non-coding RNAs (lncRNAs) respond to several extrinsic stimuli, causing changes in cancer cells by participating in multiple steps of gene expression. However, it is unclear whether lncRNAs respond to hypoxia in breast cancer and the regulatory mechanisms on their target genes. We hypothesize that lncRNAs may regulate their target genes and in turn affect breast tumor adaptation to microenvironment of alternating O2 concentrations between hypoxia and reoxygenation. Therefore, the aims of this proposal are to identify oxygen-responsive lncRNAs in breast cancer MCF-7 cells, and to delineate their regulatory mechanisms. In order to prove our hypothesis, we propose to conduct experiments with the following specific aims:

In our preliminary results, we have identified several oxygen responsive lncRNA candidates and choose NDRG1-OT1 and its target genes NDRG1 as an example to show the feasibility of this proposal. Once the regulatory mechanism of NDRG1 by NDRG1-OT1 is elucidated, similar strategy will be applied to investigate other target genes of NDRG1-OT1 or other lncRNAs. In summary, using high-throughput genomic approaches, biochemical methods, and functional assays, this proposal will allow us to get a deeper insight of the genetic mechanisms and functional roles of lncRNAs upon oxygen variation in breast 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.
 

 

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:

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.