β-Catenin in oral cancer: An update on current knowledge
Introduction
β-Catenin is a protein of the Armadillo family, and it has multiple functions that depend on its cellular localization. These functions derive from its interactions with other cellular proteins, both on the membrane and in the cytoplasm and nucleus, made possible by the presence in the molecule of a central repetitive domain [1], [2] that acts as common platform to create functional complexes with other proteins (Fig. 1).
β-Catenin forms a complex with the adhesion molecule E-cadherin, promoting cell–cell adhesion and contributing to the structural formation of the stratified squamous epithelium of the oral mucosa, also preventing the cell dissociation required for cancer invasion and progression. Besides the membrane localization, there is a dynamic pool of cytoplasmic β-catenin that serves as rapid connection between the extracellular microenvironment and nucleus through the plasma membrane [3]. Thus, cytoplasmic β-catenin acts as signal transcription factor to the nucleus in the canonical Wnt pathway, activating the transcription of genes with various cell functions [2]. Over the past few years, it has been confirmed that structural or functional alterations of β-catenin, or of the molecules with which it interacts, can promote cancer progression, either by increasing cell mobility and invasiveness secondary to the loss of cell adhesive functions, or by promoting oncogene transcription linked to a dysregulation of the canonical Wnt pathway. This review addresses the current knowledge on the implications of β-catenin in the development of oral cancer.
Section snippets
Functions of β-catenin
β-Catenin is usually located in the cell membrane, forming complexes with the adhesion molecule E-cadherin.
Oncogenic mechanisms linked to β-catenin
The cellular localization of β-catenin is an important indirect indicator of its oncogenic activity (Fig. 2). One oncogenic mechanism linked to β-catenin is relates to the loss of its adhesive function when localized on the cell membrane or to its translocation to the nucleus, where it acts as a transcription factor for different oncogenes [44]. It is therefore important to establish the topographic localization of β-catenin cellular expression in order to understand the oncogenic mechanisms.
Potential therapeutic implications
Despite the oncogenic activity of β-catenin being well-documented, there have been remarkably few attempts to manipulate it. Thus, there have been studies with molecules such as Chibby [3] and Tax-Interaction Protein-1 (TIP-1), which inhibit the interaction between β-catenin and TCF but these have been inadequate to control the high levels of stabilized β-catenin seen in cancerous cells [2]. Other small β-catenin/TCF4-inhibitor molecules have been found to lack specificity though have also
Conflict of interest statement
None declared.
References (93)
- et al.
Specific armadillo repeat sequences facilitate β-catenin nuclear transport in live cells via direct binding to nucleoporins Nup62, Nup153, and RanBP2/Nup358
J Biol Chem
(2012) - et al.
Wnt signaling from membrane to nucleus: β-catenin caught in a loop
Int J Biochem Cell Biol
(2012) - et al.
Wnt/beta-catenin signaling: components, mechanisms and diseases
Dev Cell
(2009) - et al.
Casein kinase II phosphorylation of E-cadherin increases E-cadherin/β-catenin interaction and strengthens cell–cell adhesion
J Biol Chem
(2000) - et al.
Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced
Am J Kidney Dis
(1995) - et al.
Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role
Cell
(1991) - et al.
Shisa promotes head formation through the inhibition of receptor protein maturation for the caudalizing factors, Wnt and FGF
Cell
(2005) - et al.
Pygopus and legless provide essential transcriptional coactivator functions to armadillo/beta-catenin
Curr Biol
(2005) - et al.
Transcription under the control of nuclear Arm/beta-catenin
Curr Biol
(2006) - et al.
Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling
Cell
(2008)
The APC protein and E-cadherin form similar but independent complexes with alpha-catenin, beta-catenin, and plakoglobin
J Biol Chem
Inactivation of the E-cadherin mediated cell adhesion system in human cancers
Am J Pathol
E-cadherin in non-tumor epithelium adjacent to oral cancer as risk marker for the development of multiple tumors
Br J Oral Maxillofac Surg
Methylation patterns of the E-cadherin 5′ CpGisland are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression
J Biol Chem
Prognostic significance of the Wnt pathway in squamous cell laryngeal cancer
Oral Oncol
Abnormal beta-catenin expression in oral cancer with no gene mutation: correlation with expression of cyclin D1 and epidermal growth factor receptor, Ki-67 labeling index, and clinicopathological features
Hum Pathol
Expression of beta-catenin in rat oral epithelial dysplasia induced by 4-nitroquinoline 1-oxide
Oral Oncol
Wnt-3A/β-catenin signaling induces transcription from the LEF-1 promotor
J Biol Chem
Alterations of adenomatous polyposis coli (APC) gene in oral squamous cell carcinoma
Int J Oral Maxillofac Surg
Expression of epithelial cadherin and alpha- and beta-catenins in nontumoral livers and hepatocellular carcinomas
Hepatology
Loss of heterozygosity involving the APC gene in oral squamous cell carcinomas
Oral Surg Oral Med Oral Pathol
Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex
Cancer Cell
Capsaicin represses transcriptional activity of β-catenin in human colorectal cancer cells
J Nutr Biochem
Streptonigrin inhibits β-Catenin/Tcf signaling and shows cytotoxicity in β-catenin-activated cells
Biochim Biophys Acta
Protein kinase CKII regulates the interaction of β-catenin with α-catenin and its protein stability
J Cell Sci
E-cadherin/β-catenin complex and the epithelial barrier
J Biomed Biotechnol
Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/β-catenin complex in cells transformed with a temperature-sensitive v-SRC gene
J Cell Biol
β-catenin interacts with low-molecular-weight protein tyrosine phosphatase leading to cadherin-mediated cell–cell adhesion increase
Cancer Res
E-cadherin and APC compete for the interaction with β-catenin and the cytoskeleton
J Cell Biol
Essential role of BCL9-2 in the switch between β-catenin’s adhesive and transcriptional functions
Genes Dev
Cables links Robo-bound Abl kinase to N-cadherin-bound β-catenin to mediate Slit-induced modulation of adhesion and transcription
Nat Cell Biol
Central role for Rho in TGF-β1-induced α-smooth muscle actin expression during epithelial–mesenchymal transition
Am J Physiol Renal Physiol
TGF-β1-mediated alterations of renal proximal tubular epithelial cell phenotype
Am J Physiol Renal Phsysiol
E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium
Proc Natl Acad Sci USA
The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression
Nat Cell Biol
The basics of epithelial–mesenchymal transition
J Clin Invest
Transactivation of vimentin by betacaten in human breast cancer cells
Cancer Res
Beta-catenin destruction complex: insights and questions from a structural perspective
Oncogene
LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way
Development
Beyond Wnt inhibition: new functions of secreted frizzled-related proteins in development and disease
J Cell Sci
Diversity of LEF/TCF action in development and disease
Oncogene
Wnt signalling: variety at the core
J Cell Sci
The ins and outs of APC and beta-catenin nuclear transport
EMBO Rep
A unique DNA binding domain converts T-cell factors into strong Wnt effectors
Mol Cell Biol
Regulation of β-catenin nuclear dynamics by GSK-3β involves a LEF-1 positive feedback loop
Traffic
PITX2 and beta-catenin interactions regulate Lef-1 isoform expression
Mol Cell Biol
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