Nuclear expression of Glycogen synthase kinase‐3β and lack of membranous β‐catenin is correlated with poor survival in colon cancer

Abstract

Dysregulation of Wnt/b-catenin signaling is a hallmark of colon cancer. Glycogen synthase kinase-3b (GSK-3b) can be a positive regulator of survival and proliferation of cultured colon cancer cell but its role in clinical colon cancer is unknown. Our objectives were to evaluate the role of GSK-3b in colon cancer. A tumor tissue microarray of primary colon cancers and metastases was used to evaluate expression and subcellular localization of GSK-3b and b-catenin. In total, 85 primary colon cancer samples were evaluated by immunohistochemistry. Immunoreactivity was correlated to known markers of adverse prognosis. Overall survival was the primary end-point. We found nuclear accumulation of GSK-3b in 39% (33/85) of evaluated tumors. Nuclear GSK-3b was significantly associated with shorter overall survival (p 5 0.008), larger tumor size (p 5 0.015), distant metastasis (p 5 0.029) and loss of membranous b-catenin (p 5 0.007). Loss of membranous b-catenin occurred in 37% (30/82) of the tumors and was associated with poor survival (p 5 0.016). The combination of nuclear GSK-3b and lack of membrane b-catenin occurred in a total of 26% of the studied tumors (21/61) and was significantly and independently associated with poor prognosis. Our results suggest that nuclear expression of GSK-3b and loss of membrane b-catenin identify a subset of colon carcinomas with worse prognosis.Colorectal cancer (CRC) is the third most common cancer worldwide, with over one million cases occurring every year. The mortality rate for CRC is approximately half of its global incidence. Five-year survival estimate for CRC exceeds 50%, but is highly variable depending on the stage of the disease. 1 The etiological factors and pathogenic mechanisms underlying the development of CRC are complex and heterogeneous and include inflammation, with inflammatory bowel disease being associated with an increased risk of CRC; dietary and life style factors, such as diets rich in red meat and unsaturated fat, excessive alcohol consumption and reduced physical activity. 2 Further, it is estimated that 15-30% of patients have a major hereditary component, only a quarter of which can be attributed to hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis. 3 Wnt signaling is one of the key signaling pathways controlling proliferation, differentiation and morphogenesis of cells during development. In all, >90% of CRCs have a mutation in a key regulatory factor of the Wnt/b-catenin pathway, most often in APC or b-catenin, resulting in activation of the pathway. 4 Wnt signaling is initiated by the binding of Wnt family members to a receptor complex consisting of the Frizzled family of transmembrane receptors, together with the coreceptors LRP5/6. Wnt signaling inactivates GSK-3b and prevents it from phosphorylating b-catenin, and thus stabilizing b-catenin in the cytoplasm. As b-catenin accumulates, it translocates into the nucleus where it binds to T-cell-specific transcription factor (TCF)/LEF and increases transcription of proto-oncogenes s...

GSK-3β–Regulated N-Acetyltransferase 10 Is Involved in Colorectal Cancer Invasion

“…This may be due to difficulty in defining the status of GSK-3b by immunohistochemistry, as at this time there is no established standard for evaluation of GSK-3b staining. Moreover, abnormal nuclear staining of GSK-3b, which is described in a previous study, was not found in this study (22).…”

“…GSK-3b showed weak staining in the cytoplasm or membrane of normal glandular epithelia (defined as normal), but cancer cells showed either negative staining (À), or showed focal overstaining (þ). Nuclear staining of GSK-3b was not observed, which differs from what was described in a previous report (22). Stained slides were reviewed separately by two independent reviewers blinded to the clinical data.…”

“…Complete loss of GSK-3b staining was seen in 144 of 222 (64.9%) samples, and 69 (69 of 222; 31.1%) cases showed focal overstaining, but no nuclear staining was found as has been reported earlier (ref. 22; Supplementary Table S4). Neither loss of expression nor overexpression of GSK-3b correlated with cytoplasmic or membranous NAT10 staining (P ¼ 0.795, or 0.872, respectively; see Discussion).…”

Glycogen synthase kinase-3: A potential preventive target for prostate cancer management

“…Recent studies showed that elevated levels of GSK-3 protein or activation (tyrosine α-279/β-216 phosphorylation) were associated with adverse prognosis in patients with lung cancer (positive in 41% cases) [68], gastric cancer (44%) [69] and glioblastoma (55%) [70]. GSK-3β protein nuclear accumulation was found in the majority of solid malignancies such colon cancers (39%) [71], pancreatic cancers (51%) [72], urinary bladder cancer (62% non-invasive or 91% invasive TCC) [73], renal cancers (91.89%) [74]. In contrast, GSK-3β serine-9 inactive phosphorylation was found in 47.2% breast cancers and was significantly correlated with a worse clinical outcome [75].…”

6-Bromoindirubin-3′oxime (BIO) decreases proliferation and migration of canine melanoma cell lines

“…The presence of active GSK-3β has been associated with an improved prognosis in breast cancer, while reduced GSK-3β expression in hepatic cancers was associated with a poor prognosis (Quintayo et al, 2012; Huang et al, 2013). However, recent work suggests its presence or hyperactivation plays an oncogenic role in other human cancers, such as colon cancer, osteosarcoma, gliomas, and malignant melanoma (Kotliarova et al, 2008; Tang et al, 2012; Madhunapantula et al, 2013; Salim et al, 2013; Tsai et al, 2013). The role of GSK-3β in canine malignant melanoma, however, has not yet been defined.…”