Dietary zinc (Zn)-deficiency is implicated in the pathogenesis of human oral-esophageal cancer. In rodents Zn-deficiency induces a hyperplastic phenotype in tongue and esophagus by causing cell proliferation and changes in gene expression. Zn-deficient (ZD) rats are very sensitive to chemically-induced esophageal and tongue carcinogenesis. Zn-replenishment (ZR) reverses cell proliferation, corrects abnormal gene expression, and inhibits tumorigenesis. Our long-term goal is to delineate the biological role of Zn nutrition in oral- esophageal cancer development and prevention, using our well-characterized ZD rodent cancer models. MicroRNAs (miRNAs) are a diverse class of small non-coding RNAs that post-transcriptionally regulate the expression of target mRNA transcripts. Recent evidence shows that alterations in miRNA gene expression contribute to the pathogenesis of most human cancers. Dietary modulation of miRNA expression in carcinogenesis, however, is an under-investigated research area. Our preliminary data show that a ZD diet induces a distinct miRNA signature in hyperplastic ZD versus Zn-sufficient (ZS) esophagus with prominent upregulation of miR-31. During N-nitrosomethylbenzylamine (NMBA)-induced esophageal carcinogenesis, miR-31 overexpression is sustained in ZD esophagi with a high tumor outcome but is repressed in ZR esophagi with a low tumor outcome. Importantly, in vivo administration of locked nucleic acid (LNA)-anti-miR- 31 oligonucleotide to ZD rats effectively knockdowns miR-31 expression in the esophagus and blood, accompanied by reduction in esophageal cell proliferation. These data suggest that dysregulation of miR-31 expression may be a mechanism underlying the biological effects of Zn-deficiency. miR-31 is overexpressed in several human cancers, including tongue squamous cell carcinoma, oral cancer, lung cancer, colorectal cancer, and hepatocellular carcinoma. Interestingly, miR-31 can use multiple mechanisms to promote tumor growth, but oppose breast cancer metastasis. Based on these observations and our preliminary data, we propose two Aims.
Aim 1. Elucidate the role of miR-31 in Zn-deficiency driven esophageal preneoplasia. We will (a) identify downstream target genes of miR-31 that are biologically relevant to initiation of tumorigenesis;(b) determine if in vivo silencing of miR-31 attenuates the hyperplastic ZD esophageal phenotype by reducing cell proliferation, increasing apoptosis, and modulating expression of validated miR-31 target genes;and (c) identify global gene expression changes following in vivo knockdown of miR-31 by comparing mRNA profiles of esophageal mucosa from LNA-anti-miR-31 treated ZD rats, LNA-miR-31-mismatch treated ZD rats, saline- treated ZD rats, and saline-treated ZS rats.
Aim 2. Test the hypothesis that in vivo knockdown of miR-31 counteracts the effect of ZD and inhibits esophageal tumorigenesis by NMBA. Results from this proposal will provide mechanistic insights into the process by which Zn-deficiency promotes esophageal carcinogenesis, as well as advance the understanding of the molecular role of miR-31 in cancer development and prevention.

Public Health Relevance

Given the prevalence of dietary zinc-deficiency, our studies that determine how zinc influences microRNA expression in esophageal cancer development and prevention are of clinical importance. Results from the proposed research will advance the understanding of the biological role of zinc and miR-31 in cancer development and prevention, as well as identify new microRNA species, for improved cancer prevention, diagnosis, and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA152505-01A1
Application #
8114422
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Emenaker, Nancy J
Project Start
2011-03-01
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
1
Fiscal Year
2011
Total Cost
$202,145
Indirect Cost
Name
Thomas Jefferson University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Fong, Louise Y; Taccioli, Cristian; Jing, Ruiyan et al. (2016) MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency. Oncotarget 7:10723-38
Taccioli, Cristian; Garofalo, Michela; Chen, Hongping et al. (2015) Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo. J Natl Cancer Inst 107:
Alder, Hansjuerg; Taccioli, Cristian; Chen, Hongping et al. (2012) Dysregulation of miR-31 and miR-21 induced by zinc deficiency promotes esophageal cancer. Carcinogenesis 33:1736-44