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Principal Investigator: Antonis Kourtidis
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $465,803
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Colorectal abnormalities such as pre-cancerous fibrotic disease and colon cancer are prevalent. However, the
mechanisms that link the extensive extracellular matrix (ECM) remodeling that occurs during fibrosis to pro-
tumorigenic cell transformation are still poorly understood. Compromised epithelial integrity is a common feature
of these colorectal conditions. Recently, we discovered a mechanism that links epithelial tissue integrity with the
RNA interference (RNAi) machinery, miRNA regulation, and colon cell behavior. We have shown that the
adherens junctions, which is an essential architectural component of the cell, recruit the microprocessor and the
RNAi-induced silencing complex (RISC), the core components of the RNAi machinery, as well as a specific set
of miRNAs and mRNAs, in colon epithelial cells. This interaction occurs through PLEKHA7, a member of the E-
cadherin cell-cell adhesion complex. PLEKHA7 loss results in compromised epithelial integrity, decreased levels
and silencing activity of a set of miRNAs, increased oncogene expression and pro-tumorigenic cell
transformation. We have also found extensive dysregulation of PLEKHA7 and of the junctional RNAi machinery
in colon cancer cell lines and tumor patient samples. Colon epithelial tissues undergo abnormal physical stress
during fibrosis and colon cancer due to excessive ECM remodeling, which promotes disease progression.
Interestingly, our preliminary data reveal that application of physical stress to colon epithelial cells through the
ECM results in mis-localization of the junctional RNAi machinery. We also have preliminary evidence that
disruption of the junctional RNAi results in overexpression of ECM remodeling regulators and promotes ECM
remodeling and cell migration. We hypothesize that biomechanical cues from the ECM result in dysregulation of
PLEKHA7 and its associated RNAi machinery at the adherens junctions, promoting oncogene expression, further
ECM remodeling, and pro-tumorigenic cell behavior. We will examine our hypothesis under two specific Aims:
1) Physical cues from the ECM regulate PLEKHA7-RNAi complex formation and function at adherens junctions;
2) PLEKHA7-associated miRNAs regulate ECM remodeling and pro-tumorigenic cell behavior. This study is
significant, since it investigates a novel mechanistic link between physical changes in the ECM, epithelial
integrity, and colon epithelial cell behavior through a localized function of the RNAi machinery. The proposed
work is innovative by introducing the concept of a mechanosensitive RNAi machinery at adherens junctions. The
impact of the study is that it will advance our understanding of the underlying mechanistic causes of intestinal
diseases, particularly those connecting fibrotic conditions to pro-tumorigenic cell transformation. Since this
involves miRNA regulation as the focal point in the crosstalk between ECM and colon cell behavior, the study
can lead to future development of RNA-based therapeutics.
Terms: <Acceleration><Actins><Adherens Junction><Adhering Junction><Adhesive Junction><Anchoring Junction><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Architecture><Assay><Binding><Bioassay><Biological Assay><Biomechanics><Body Tissues><Cadherin-1><Cancer Genes><Cancer-Promoting Gene><Cancers><Cell Body><Cell Components><Cell Locomotion><Cell Migration><Cell Movement><Cell Structure><Cell-Cell Adhesion><Cell-Extracellular Matrix><Cells><Cellular Expansion><Cellular Growth><Cellular Matrix><Cellular Migration><Cellular Motility><Cellular Structures><Colon><Colon Cancer><Colon Carcinoma><Colon Neoplasms><Colon Tumor><Colon or Rectum><Colonic Diseases><Colonic Mass><Colonic Neoplasms><Colonic Tumor><Colorectal><Complex><Cues><Cytoskeletal System><Cytoskeleton><Data><Deposit><Deposition><Development><Disease><Disease Progression><Disorder><E-Cadherin><ECM><Engineering / Architecture><Epithelial Calcium-Dependent Adhesion Protein><Epithelial Cells><Epithelial-Cadherin><Epithelium><Extracellular Matrix><Fibrosis><Future><High Prevalence><Image><In Vitro><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Intestinal Diseases><Intestinal Disorder><Link><Malignant Neoplasms><Malignant Tumor><Mechanical Stress><Mediating><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Micro RNA><MicroRNAs><Microprocessor><Molecular Interaction><Neoplasm Metastasis><Non-Polyadenylated RNA><Oncogenes><Oncogenesis><Organoids><Patients><Polyps><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proteins><RNA><RNA Gene Products><RNA Interference><RNA Silencing><RNA based therapeutics><RNA based therapy><RNA therapy><RNAi><Regulation><Reporting><Ribonucleic Acid><Risk Factors><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Sequence-Specific Posttranscriptional Gene Silencing><Stress><Structure><Testing><Tissues><Transforming Genes><Up-Regulation><Upregulation><Uvomorulin><Work><biomechanical><cancer in the colon><cancer metastasis><cancer progression><cell behavior><cell growth><cell motility><cell transformation><cellular behavior><colon cancer cell line><colon disorder><colon neoplasia><colorectal cancer cell line><colorectum><developmental><imaging><in vivo Model><inflammatory disease of the intestine><inflammatory disorder of the intestine><innovate><innovation><innovative><insight><intestinal autoinflammation><intestine disease><intestine disorder><intracellular skeleton><loss of function><mRNA><malignancy><mechanical cue><mechanical signal><member><miRNA><miRNAs><neoplasm progression><neoplasm/cancer><neoplastic progression><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><overexpress><overexpression><precancer><precancerous><premalignant><programs><recruit><social role><therapeutic RNA><tool><transformed cells><tumor><tumor cell metastasis><tumor growth><tumor progression><tumorigenesis><tumorigenic>