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

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, ?-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/?-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. Apc^Min/+ mice when infected with CR and BLT1^-/-;Apc^Min/+ 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.

SUBMITTER: Roy BC

PROVIDER: S-EPMC6481322 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Roy Badal Chandra BC Ahmed Ishfaq I Ramalingam Satish S Jala Venkatakrishna V Haribabu Bodduluri B Ramamoorthy Prabhu P Ashcraft John J Valentino Joseph J Anant Shrikant S Sampath Venkatesh V Umar Shahid S

Oncotarget 20190322 24

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 ...[more]

PMID: 31040926

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Project description:Background and aimsCholangiocarcinoma (CCA) is a very aggressive cancer showing the presence of high cancer stem cells (CSCs). Doublecortin-like kinase1 (DCLK1) has been demonstrated as a CSC marker in different gastroenterological solid tumors. Our aim was to evaluate in vitro the expression and the biological function of DCLK1 in intrahepatic CCA (iCCA) and perihilar CCA (pCCA).Approach and resultsSpecimens surgically resected of human CCA were enzymatically digested, submitted to immunosorting for specific CSC markers (LGR5 [leucine-rich repeat-containing G protein-coupled receptor], CD [clusters of differentiation] 90, EpCAM [epithelial cell adhesion molecule], CD133, and CD13), and primary cell cultures were prepared. DCLK1 expression was analyzed in CCA cell cultures by real-time quantitative PCR, western blot, and immunofluorescence. Functional studies have been performed by evaluating the effects of selective DCLK1 inhibitor (LRRK2-IN-1) on cell proliferation (MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay, cell population doubling time), apoptosis, and colony formation capacity. DCLK1 was investigated in situ by immunohistochemistry and real-time quantitative PCR. DCLK1 serum concentration was analyzed by enzyme-linked immunosorbent assay. We describe DCLK1 in CCA with an increased gene and protein DCLK1 expression in pCCALGR5+ and in iCCACD133+ cells compared with unsorted cells. LRRK2-IN-1 showed an anti-proliferative effect in a dose-dependent manner. LRRK2-IN-1 markedly impaired cell proliferation, induced apoptosis, and decreased colony formation capacity and colony size in both iCCA and pCCA compared with the untreated cells. In situ analysis confirmed that DCLK1 is present only in tumors, and not in healthy tissue. Interestingly, DCLK1 was detected in the human serum samples of patients with iCCA (high), pCCA (high), HCC (low), and cirrhosis (low), but it was almost undetectable in healthy controls.ConclusionsDCLK1 characterizes a specific CSC subpopulation of iCCACD133+ and pCCALGR5+ , and its inhibition exerts anti-neoplastic effects in primary CCA cell cultures. Human DCLK1 serum might represent a serum biomarker for the early CCA diagnosis.

Dataset Information

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

Publications

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

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