Research Papers:

Co-localization of autophagy-related protein p62 with cancer stem cell marker dclk1 may hamper dclk1’s elimination during colon cancer development and progression

Badal Chandra Roy, Ishfaq Ahmed, Satish Ramalingam, Venkatakrishna Jala, Bodduluri Haribabu, Prabhu Ramamoorthy, John Ashcraft, Joseph Valentino, Shrikant Anant, Venkatesh Sampath and Shahid Umar _

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Oncotarget. 2019; 10:2340-2354. https://doi.org/10.18632/oncotarget.26684

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Badal Chandra Roy1,*, Ishfaq Ahmed1,*, Satish Ramalingam3, Venkatakrishna Jala4, Bodduluri Haribabu4, Prabhu Ramamoorthy2, John Ashcraft1, Joseph Valentino1, Shrikant Anant1, Venkatesh Sampath5 and Shahid Umar1

1Departments of Surgery and Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA

2Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA

3Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, Kattankulathur, Kanchipuram, Tamil Nadu, India

4James Graham Brown Cancer Center and Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA

5Division of Neonatology, Children’s Mercy Hospital, Kansas City, MO, USA

*These authors have contributed equally to this work

Correspondence to:

Shahid Umar, email: [email protected]

Keywords: colon cancer; autophagy; stem cells; dclk1; metastasis

Received: January 10, 2019     Accepted: February 01, 2019     Published: March 22, 2019


Autophagy may play a critical role in colon cancer stem cells (CCSCs)-related cancer development. Here, we investigate whether accumulation of infection/injury-induced CCSCs due to impaired autophagy influences colon cancer development and progression. When Apc++ mice were infected with Citrobacter rodentium (CR; 109CFUs), we discovered presence of autophagosomes with increases in Beclin-1, LC3B and p62 staining during crypt hyperplasia. Apc1638N/+ mice when infected with CR or subjected to CR+AOM treatment, exhibited increased colon tumorigenesis with elevated levels of Ki-67, β-catenin, EZH2 and CCSC marker Dclk1, respectively. AOM/DSS treatment of Apc1638N/+ mice phenocopied CR+AOM treatment as colonic tumors exhibited pronounced changes in Ki-67, EZH2 and Dclk1 accompanied by infiltration of F4/80+ macrophages, CD3+ lymphocytes and CD3/β-catenin co-localization. Intestinal and colonic tumors also stained positive for migrating CSC markers CD110 and CDCP1 wherein, colonic tumors additionally exhibited stromal positivity. In tumors from CR-infected, CR+AOM or AOM/DSS-treated Apc1638N/+ mice and surgically-resected colon tumor/metastatic liver samples, significant accumulation of p62 and it’s co-localization with LC3B and Dclk1 was evident. ApcMin/+ mice when infected with CR and BLT1-/-;ApcMin/+ mice, exhibited similar co-localization of p62 with LC3B and Dclk1 within the tumors. Studies in HCT116 and SW480 cells further confirmed p62/Dclk1 co-localization and Chloroquin/LPS-induced increases in Dclk1 promoter activity. Thus, co-localization of p62 with Dclk1 may hamper Dclk1’s elimination to impact colon cancer development and progression.

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