Increased Expression of -Catenin, Phosphorylated Glycogen Synthase Kinase 3 , Cyclin D1, and c-myc in Laterally Spreading Colorectal Tumors

Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
Journal of Histochemistry and Cytochemistry (Impact Factor: 1.96). 12/2008; 57(4):363-371. DOI: 10.1369/jhc.2008.953091


Laterally spreading tumors (LSTs) are considered a special subtype of superficial colorectal tumor. This study was performed to characterize the clinicopathological features and examine activation of the Wnt/beta-catenin pathway in LSTs and protruded-type colorectal adenomas (PAs). Fifty LSTs and 54 PAs were collected, and their clinicopathological characteristics were compared. The expression of E-cadherin, beta-catenin, glycogen synthase kinase-3beta (GSK-3beta), phosphorylated GSK-3beta, (phospho-GSK-3beta), cyclin D1, and c-myc was investigated by immunohistochemical staining on serial sections. Patients with LSTs were significantly older than those bearing PAs (63.4 vs 47.4 years old; p<0.001). The mean size of LSTs was significantly larger than that of PAs (27.0 mm vs 14.6 mm; p<0.01). Forty-eight percent of LSTs were located in the proximal colon, which was significantly higher than that of PAs (18.5%; p<0.05). Expression of beta-catenin, phospho-GSK-3beta, cyclin D1, and c-myc was significantly increased in LSTs compared with PAs (p<0.05). However, E-cadherin and total GSK-3beta expression was not significantly different between the two groups. The level of beta-catenin expression correlated strongly with phospho-GSK-3beta, cyclin D1, and c-myc expression in LSTs but not in PAs. Our findings suggest that activation of the Wnt/beta-catenin pathway is more prevalent in LSTs than in PAs, suggesting that phosphorylation-dependent inactivation of GSK-3beta may be involved in LST carcinogenesis.

Download full-text


Available from: Bin Jiang, Dec 10, 2014
  • Source
    • "Hashimoto et al (23) showed that β-catenin in LSTs is expressed more intensely in flat structure segments or invasive lesions than in granulation structures or intramucosal lesions. Wang et al (24) also reported that β-catenin is expressed more prominently in LSTs than in protruded-type adenoma. The authors evaluated the β-catenin expression by counting stained cells and did not report the distribution of β-catenin in the nucleus, cytoplasm or cell membrane. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal flat-type tumors include laterally spreading tumors (LSTs) and flat depressed-type tumors. The former of which shows a predominant lateral spreading growth rather than an invasive growth. The present study examined the morphological characteristics of LSTs, in comparison with polypoid- or flat depressed-type tumors, along with the expression of atypical protein kinase C (aPKC) λ/ι, a pivotal cell polarity regulator, and the hallmarks of cell polarity, as well as with type IV collagen, β-catenin and E-cadherin. In total, 37 flat-type (24 LSTs and 13 flat depressed-type tumors) and 20 polypoid-type colorectal tumors were examined. The LSTs were classified as 15 LST adenoma (LST-A) and nine LST cancer in adenoma (LST-CA). An immunohistochemical examination was performed on aPKC λ/ι, type IV collagen, β-catenin and E-cadherin. The LST-A and -CA showed a superficial replacing growth pattern, with expression of β-catenin and E-cadherin in the basolateral membrane and type IV collagen along the basement membrane. In addition, 86.6% of LST-A and 55.6% of LST-CA showed aPKC λ/ι expression of 1+ (weak to normal intensity staining in the cytoplasm compared with the normal epithelium). Furthermore, ~45% of the polypoid-type adenomas showed 2+ (moderate intensity staining in the cytoplasm and/or nucleus) and 66.7% of the polypoid-type cancer in adenoma were 3+ (strong intensity staining in the cytoplasm and nucleus). A statistically significant positive correlation was observed between the expression of aPKC λ/ι and β-catenin (r=0.842; P<0.001), or type IV collagen (r=0.823; P<0.001). The LSTs showed a unique growth pattern, different from the expanding growth pattern presented by a polypoid tumor and invasive cancer. The growth characteristics of LST appear to be caused by adequate coexpression of β-catenin, type IV collagen and aPKC λ/ι.
    Oncology letters 09/2014; 8(3):977-984. DOI:10.3892/ol.2014.2271 · 1.55 Impact Factor
  • Source
    • "IHC was performed on TMA tissue sections that were depffinized. After target retrieval, sections were incubated with primary antibodies for p16 (Roche mtm laboratories AG, Heidelberg, Germany) [12] and cyclin D1 (Cell Signaling, Ontario, Canada) [13] with duration and temperature specified for each marker (Table 1). The sections were then incubated with the EnVision+ System (DAKO Corporation) for cyclin D1 for detection of antigen-antibody reactions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To determine the biological characteristics of oropharyngeal squamous cell carcinoma (OpSCC) and related outcome. Retrospective study. Patients (N=60) with primary OpSCC from 2000 to 2005 were retrospectively identified from Pathology database and the outcome was confirmed through chart review. Among these, 41 biopsy samples with enough tissues were retrieved to construct a tissue microarray for detection of the presence of high-risk human papillomavirus (HPV) using Chromogenic in situ hybridization (CISH) as well as the expression of p16 and cyclin D1 using immunohistochemistry. Main outcome measures Disease-free survival. Among 60 patients, 39 (65%) patients had no recurrence or died without disease at the last follow-up (disease-free survival or Group 1), and 21 (35%) patients had persistent disease or died of disease (progression-free survival or Group 2). Although follow-up time was twice as long in group 1 (4.7 ± 2.2 vs. 2.0 ± 1.6 years; P < 0.0001), there was no difference between the 2 groups in age, gender, smoking/alcohol habits, TNM staging and treatment modalities. Among those 41 cases with available tumour tissues, there was no difference in HPV status and p16 expression between the 2 groups but a significant difference in cyclin D1 expression (P = 0.05). Using Kaplan-Meir survival analysis and log-rank test, cyclin D1 overexpression was highly associated with a poor prognosis when comparing time to outcome (P < 0.0001). Cyclin D1 overexpression is a potential prognostic marker of OpSCC.
    Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale 03/2013; 42(1):23. DOI:10.1186/1916-0216-42-23 · 0.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cadherins belong to a family of Ca(2+)-dependent homophilic cell-cell adhesion proteins that are important for correct cellular localization and tissue integrity. They play a major role in the development and homeostasis of epithelial architecture. Recently, it has become more and more evident that P-cadherin contributes to the oncogenesis of many tumors. To analyze the role of P-cadherin in oral squamous cell carcinoma (OSCC), we used a cell line that was deficient of the classical cadherins, P-cadherin, E-cadherin and N-cadherin. This cell line was transfected with full-length P-cadherin (PCI52_PC). After overexpression of P-cadherin, PCI52_PC gained an epithelial-like brickstone morphology in contrast to the mock-transfected cells with a spindle-shaped mesenchymal morphology. Immunohistochemical analysis revealed a strong nuclear Snail staining in mock-transfected cells compared with a significantly reduced nuclear staining and translocation to the cytoplasm in P-cadherin-overexpressing cells. Interestingly, the effects triggered by P-cadherin overexpression could be reversed by transfecting the cells with an antisense P-cadherin plasmid construct. Additional investigations showed a reexpression of E-cadherin in all P-cadherin-transfected cell clones in contrast to the mock controls. Analyzing the signaling mechanism behind it, we found glycogen-synthase-kinase-3beta (GSK-3beta) bound to Snail in all cell clones. Furthermore, P-cadherin-overexpressing cell lines showed activated GSK-3beta that phosphorylated Snail leading to its cytoplasmic translocation. In summary, our results reveal P-cadherin as one major component in reconfiguring mesenchymal cells with epithelial features by triggering GSK-3beta-mediated inactivation and cytoplasmatic translocation of Snail in OSCC.
    Carcinogenesis 08/2009; 30(10):1781-8. DOI:10.1093/carcin/bgp175 · 5.33 Impact Factor
Show more