国外大学申请Proposal

Coding-independent regulation of colon cancer cell proliferation

PROJECT DESCRIPTION

Colorectal Cancer (CRC), a malignant disease derived from colon epithelial cells, is one of the major threats to public health. Australia has one of the highest rates of CRC in the world. It is the third most common type of newly diagnosed cancer in the country. Moreover, it is the second most common cancer killer, claiming lives of around 3982 Australians each year. However, there is currently no curative treatment for metastatic colorectal cancers. Investigation of genes and signaling pathways that are dysregulated in CRC is a high priority for identification of novel therapeutic targets.

Only 1.5% of the mammalian genome encodes proteins, and most of the genome is transcribed to tens of thousands of long (>200 nt) non-coding RNAs (lncRNAs). However, the functional consequence of the expression of lncRNAs has been largely uncharacterized. To date, a very small number of lncRNAs have been investigated, and their functional roles, revealed, in colon cancer.

Preliminary studies from Professor Xu D ong Zhang’s laboratory have shown that the expression of a lncRNA called REG1CP is elevated in five CRC tissues in comparison with adjacent non-cancerous colon epithelial tissues. The increase in REG1CP is further confirmed in a panel of CRC cell lines compared with a normal human colon cell line FHC. Of note, inhibition of REG1CP by siRNA reduced, whereas overexpression of REG1CP enhanced, CRC cell proliferation.

To turn this information into our advantage in understanding CRC biology and in the treatment of the disease, we propose in this application to clarify the consequence of REG1CP upregulation and the mechanism involved in CRC cells, and to examine whether REG1CP-mediated signal is a potential therapeutic target in CRC. Our specific aims are to test whether targeting REG1CP inhibits proliferation of CRC cells and retards CRC xenograft growth in animal models, and to define the mechanism that drives the increase in REG1CP expression in CRC cells and the mechanism by which REG1CP regulates colon cancer growth.

University of Newcastle has a strong cancer research program aiming to translate scientific advances into better clinical care. This project fits perfectly to the objectives of Cancer Program in that it will potentially lead to the development of new treatment approaches for CRC. Professor Xu Dong Zhang’s laboratory is highly experienced in similar studies, and it is well equipped with techniques and other materials and support needed for carrying out this project.

Background:

lncRNA: It has been recently shown that over 70% of the genomes of human and higher eukaryotes are transcribed, but only 1.5% of the human genome codes for proteins. lncRNAs are a large and diverse class of transcribed RNA molecules of more than 200 nucleotides that do not encode proteins, which may exert their functions either by binding to DNA or RNA in a sequence specific manner or by binding to proteins.

lncRNA in cancer: Increasing evidence shows that lncRNAs play an important role in cancer biology. Dysregulated expression of lncRNAs in cancer frequently marks disease progression and often serves as an independent predictor for poor prognosis of cancer patients. (1, 2)

REG1CP:REG1CP is an RNA that lacks an open reading frame. It is located to the locus enriched with regenerating (REG) gene family members, whose expression levels are closely associated with the survival rate of CRC patients (3). Interestingly, we have found REG1CP expression levels are positively related with the levels of REG gene family members including REG1A, REG1B and

REG3A, suggesting that REG1CP may plays an important role in CRC patient survival as well. Supporting data:

lncRNA microarray data showed that REG1CP was the most significantly upregulated lncRNA in five CRC tissues compared with adjacent non-cancerous colon epithelial tissues. While overexpression of REG1CP promotes, inhibition of REG1CP reduces, CRC cell proliferation. Moreover, REG1CP is also commonly upregulated in cultured CRC cell lines irrespective of their origins and genetic backgrounds in comparison with the cultured normal colon epithelial cell line FHC. Of note, REG1CP expression is positively associated with REG family members, which have been reported as predictors of poor CRC patient survival.