The ultimate goal of this project is to elucidate the molecular and cellular regulatory mechanisms of miR-140 in colon cancer. Human colon cancer is highly heterogeneous, and systemic drug treatment is almost never able to cure individuals with late stage tumors. One major reason for the failure of chemotherapy is the resistant cancer stem cell population: current chemotherapeutics target rapidly dividing cancer cells, but cancer stem cells divide slowly, and thus are relatively resistant to cytotoxic systemic therapies. Our recent studies showed that several non-coding miRNAs are involved in the resistance mechanism in colon cancer stem cells. In particular, we demonstrated that the cell proliferation of differentiated colon cancer cells was significantly reduced by over- expressing miR-140. As a result, these cells became more resistant to 5-fluorouracil (5-FU) or methotrexate (MTX) treatment. We further revealed that the expression of miR-140 was elevated in a small population of CD133+HICD44+HI colon cancer stem-like cells. These cells are highly resistant to 5-FU treatment, and by blocking miR-140 activity using anti-miR140 oligonucleotides, we were able to increase chemosensitivity to 5-FU (1). We also discovered that one of the key targets of miR-140 is histone deacetylase 4 (HDAC4), implying that miR-140 could potentially modulate transcriptional activation of genes involved in cell cycle control through HDAC4. Given the potential of this new paradigm whereby miRNAs, acting post-transcriptionally, can impact pathways leading to cancer growth and altered chemosensitivity, to offer new options for treatment, it is essential to follow up and extend our findings: We therefore propose three specific aims: (1) To investigate the mechanisms of miR-140 in contributing to proliferation, differentiation and chemoresistance in CD133+HICD44+HI colon cancer stem cells in vitro and in vivo;(2) To investigate the impact of miR-140 on colon cancer metastasis;and (3) To define the molecular targets and interaction networks impacted by miR-140, taking advantage of a powerful new approach, TrIP-Seq, to identify miRNA regulation at the translational level, even in small stem cell populations. This proposed project will provide the molecular basis for developing miR-140-based therapeutic strategies to overcome chemoresistance in colon cancer stem cells and to improve patient survival.

Public Health Relevance

This project will help to develop a new paradigm in our current understanding of the tumor biology as it relates to miR-140 function. This, in turn, may lead to the development of novel targeted therapies to colon cancer stem cells and enhance our understanding of chemoresistance in cancer, which fits the scope of the National Cancer Institute's mission to eliminate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Arya, Suresh
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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Fesler, Andrew; Guo, Shixiang; Liu, Hua et al. (2017) Overcoming chemoresistance in cancer stem cells with the help of microRNAs in colorectal cancer. Epigenomics 9:793-796
Yang, Jie; Ma, Dongling; Fesler, Andrew et al. (2017) Expression analysis of microRNA as prognostic biomarkers in colorectal cancer. Oncotarget 8:52403-52412
Fesler, Andrew; Liu, Hua; Wu, Ning et al. (2017) Autophagy regulated by miRNAs in colorectal cancer progression and resistance. Cancer Transl Med 3:96-100
Wu, Changping; Zheng, Xiao; Li, Xiaodong et al. (2016) Reduction of gastric cancer proliferation and invasion by miR-15a mediated suppression of Bmi-1 translation. Oncotarget 7:14522-36
Fesler, Andrew; Zhang, Ning; Ju, Jingfang (2016) The expanding regulatory universe of p53 in gastrointestinal cancer. F1000Res 5:756
Wu, Song; Fesler, Andrew; Ju, Jingfang (2016) Implications of Circadian Rhythm Regulation by microRNAs in Colorectal Cancer. Cancer Transl Med 2:1-6
Fesler, Andrew; Xu, Xiao; Zheng, Xiao et al. (2015) Identification of miR-215 mediated targets/pathways via translational immunoprecipitation expression analysis (TrIP-chip). Oncotarget 6:24463-73
Zhai, Haiyan; Fesler, Andrew; Ba, Yufeng et al. (2015) Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy. Oncotarget 6:19735-46
Fesler, Andrew; Jiang, Jingting; Zhai, Haiyan et al. (2014) Circulating microRNA testing for the early diagnosis and follow-up of colorectal cancer patients. Mol Diagn Ther 18:303-8
Fesler, Andrew; Zhai, Haiyan; Ju, Jingfang (2014) miR-129 as a novel therapeutic target and biomarker in gastrointestinal cancer. Onco Targets Ther 7:1481-5

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