Roles of cyclin-dependent kinase 8 and β-catenin in the oncogenesis and progression of gastric adenocarcinoma

Abstract

Abstract. Gastric adenocarcinoma is a common cause of cancer-related death. The Wnt/β-catenin pathway plays an important role in various cancers. However, relatively little is known about the regulatory mechanism of β-catenin in stomach cancer. To determine the patterns of cyclin-dependent kinase (CDK) 8 and β-catenin expression and the relationship between CDK8 and β-catenin, we conducted a study of immunohistochemical staining of tumor tissues (12 adenomas, 24 early gastric carcinomas, 24 advanced gastric carcinomas and 21 metastatic lymph nodes), together with Western blot analysis and CDK8 interference studies using gastric cancer cell lines. Gastric adenocarcinomas with CDK8 expression had distinct clinical, prognostic and molecular attributes. CDK8 expression and the delocalization of β-catenin expression showed a significant positive correlation with carcinogenesis and tumor progression, especially lymph node metastasis. Immunohistochemically, CDK8 expression in gastric adenocarcinoma was independently associated with β-catenin activation (p<0.05). β-catenin expression was suppressed by CDK8 interference in the gastric adenocarcinoma cell lines, SNU-601 and SNU-638. These data support the potential link between CDK8 and β-catenin, and suggest that CDK8 detection and β-catenin delocalization could be related to a poor prognosis. Moreover, the interference of CDK8 could be a promising therapeutic modality for gastric adenocarcinoma.

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

“…9 Interestingly, CDK8 gene expression correlates with activation of β-catenin, a core transcriptional regulator of canonical WNT signaling, in colon and gastric cancers. 10,11 CDK8 gene expression also correlates with increased mortality in colorectal, breast, and ovarian cancers; 12 furthermore CDK8 is overexpressed and essential for cell proliferation in melanoma. 13 Consistent with these reports, CDK8 is located in a region of chromosome 13 known to undergo copy number gain in ∼60% of colorectal cancers and inducible shRNA-mediated knockdown of CDK8 protein reduces the growth of HT29 and Colo205 colorectal cancer human tumor xenograft animal models harboring CDK8 gene amplification.…”

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…Moreover, elevated expression of ANLN was identified as a molecular predictor of intestinal and proliferative type gastric cancer [82] . Similarly, cyclindependent kinase 8 expression and the delocalization of b-catenin expression have shown a significant positive correlation with carcinogenesis and tumor progression, especially lymph node metastasis [83] . On the other hand, the ubiquitously distributed transcription factor Yin Yang 1 (YY1) can act either as a tumor suppressor gene or as an oncogene depending on the type of tumor.…”

Retroviral Cyclin Controls Cyclin-Dependent Kinase 8-Mediated Transcription Elongation and Reinitiation

“…An absolute increase in total CDK8 activity occurs in a majority of these cancers and correlates with increased tumor cell proliferation and low patient survival (24,47,49,51).…”

“…First, CDK8 increases levels of ␤-catenin-regulated transcription by phosphorylation of E2F1 (33,48,(50)(51)(52). Second, CDK8 kinase activity promotes efficient transcription elongation of the serum response and hypoxia-induced genes (41,44).…”

“…CDK8 is an oncogene in colon cancer, melanoma, and gastric adenocarcinoma (24,(47)(48)(49)(50)(51)). An absolute increase in total CDK8 activity occurs in a majority of these cancers and correlates with increased tumor cell proliferation and low patient survival (24,47,49,51).…”