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

Creator(s)

Badal Chandra Roy
Ishfaq Ahmed
Satish Ramalingam
Venkatakrishna Jala
Bodduluri Haribabu
Prabhu Ramamoorthy
John Ashcraft
Joseph Valentino
Shrikant Anant
Venkatesh Sampath, Children's Mercy HospitalFollow
Shahid Umar

Document Type

Article

Publication Date

3-22-2019

Identifier

DOI: 10.18632/oncotarget.26684; PMCID: PMC6481322

Abstract

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.

Journal Title

Oncotarget

Volume

10

Issue

24

First Page

2340

Last Page

2354

Keywords

autophagy; colon cancer; dclk1; metastasis; stem cells

Comments

Grant support

• R01 CA185322/CA/NCI NIH HHS/United States
• R01 CA190291/CA/NCI NIH HHS/United States
• R01 DK117296/DK/NIDDK NIH HHS/United States

This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publisher's Link: https://www.oncotarget.com/article/26684/text/

Recommended Citation

Roy BC, Ahmed I, Ramalingam S, et al. Co-localization of autophagy-related protein p62 with cancer stem cell marker dclk1 may hamper dclk1's elimination during colon cancer development and progression. Oncotarget. 2019;10(24):2340-2354. Published 2019 Mar 22. doi:10.18632/oncotarget.26684