The colon cancer (CRC) staging, at the time of disease diagnosis, is critical for patient survival, which ranges from 90% for patients with localized disease to meagre 13% for the ones with metastasis. Thus, improved understanding of the molecular regulation of CRC-progression and metastasis is critical and urgent, to develop novel therapies. In this regard, studies from our, and other laboratories, have provided strong support for a casual role for upregulated claudin- 1 expression in promoting CRC malignancy, especially metastasis. An upregulated (and mislocalized) claudin-1 expression in CRC patient samples associated predominantly with CRC metastasis to liver (58%) and lymph nodes (35%). Moreover, genetic manipulation of claudin-1 expression was sufficient to modulate metastatic ability of CRC cells lines in vitro and in vivo. Further analysis suggested essential roles of proto-oncogenes Src and EphA2 in claudin-1 mediated CRC progression. The key objectives of this proposal are to determine the roles of Src- and EphA2-signaling in fostering CRC malignancy under conditions of the dysregulated claudin- 1 expression, and preclinical testing of a novel claudin-1 inhibitor for its therapeutic efficacy in inhibiting CRC malignancy. To test our hypothesis we propose following studies:
Specific Aim - 1. To determine how dysregulated claudin-1 expression promotes dissemination of colon cancer cell and metastasis;
and Specific Aim -2. To test therapeutic efficacy of a novel anti-claudin-1 small molecule inhibitor (I-6) in inhibiting CRC malignancy. The outcome of this study are expected to have substantial impact on prevention/inhibition of CRC metastasis.

Public Health Relevance

Colorectal cancer endangers males and females of all the population however the US (the United States of America) Veterans show a higher incidence rate of colon cancer than the general population. It is estimated that each year the Veterans affairs manages and treats ~175,000 CRC patients. It is therefore an urgent necessity to find novel therapeutic strategies to curb CRC- malignancy to increase the survival for U.S. Veterans with CRC. Claudin-1, a tight junction protein, is highly upregulated in CRC and its expression correlates with CRC metastasis in colon cancer cells, mouse models and human patient population. Our aim is to understand how dysregulated claudin-1 expression affects metastatic ability of CRC cells, in order to define ways to harness its use as a target molecule to inhibit CRC-progression. Additionally, we plan to perform pre-clinical testing of a novel inhibitor effective in curbing claudin-1 dependent promotion of CRC malignancy.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Oncology C (ONCC)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Omaha VA Medical Center
United States
Zip Code
Ahmad, R; Sorrell, M F; Batra, S K et al. (2017) Gut permeability and mucosal inflammation: bad, good or context dependent. Mucosal Immunol 10:307-317
Singh, Amar B; Uppada, Srijayaprakash B; Dhawan, Punita (2017) Claudin proteins, outside-in signaling, and carcinogenesis. Pflugers Arch 469:69-75
Ahmad, R; Kumar, B; Chen, Z et al. (2017) Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy by hyperactivating Wnt/?-catenin signaling. Oncogene 36:6592-6604
Ahmad, Rizwan; Rah, Bilal; Bastola, Dhundy et al. (2017) Obesity-induces Organ and Tissue Specific Tight Junction Restructuring and Barrier Deregulation by Claudin Switching. Sci Rep 7:5125
Ahmad, Rizwan; Kumar, Balawant; Pan, Kaichao et al. (2017) HDAC-4 regulates claudin-2 expression in EGFR-ERK1/2 dependent manner to regulate colonic epithelial cell differentiation. Oncotarget 8:87718-87736
Bhat, Ajaz A; Ahmad, Rizwan; Uppada, SrijayaPrakash B et al. (2016) Claudin-1 promotes TNF-?-induced epithelial-mesenchymal transition and migration in colorectal adenocarcinoma cells. Exp Cell Res 349:119-127
Pai, Priya; Rachagani, Satyanarayana; Dhawan, Punita et al. (2016) MUC4 is negatively regulated through the Wnt/?-catenin pathway via the Notch effector Hath1 in colorectal cancer. Genes Cancer 7:154-168
Singh, Amar B; Dhawan, Punita (2015) Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact. Semin Cell Dev Biol 42:58-65
Bhat, A A; Pope, J L; Smith, J J et al. (2015) Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis. Oncogene 34:4570-80
Ahmad, R; Chaturvedi, R; Olivares-Villagómez, D et al. (2014) Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis. Mucosal Immunol 7:1340-53

Showing the most recent 10 out of 11 publications