APC Expression Research Articles

MiR-135b promotes proliferation and metastasis by targeting APC in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. The aim of our study was to investigate the functional role of microRNA-135b (miR-135b) in TNBC. A real-time polymerase chain reaction assay was used to quantify miR-135b expression levels in 90 paired TNBC tissue and adjacent normal tissue samples. Wound-healing and transwell assays were performed to evaluate the effects of miR-135b expression on the migration and invasion of TNBC cells. Luciferase reporter and western blot analyses were used to verify whether the mRNA encoding APC is a major target of miR-135b. In the current study, we found that miR-135b was highly expressed in TNBC tissue and cells, and the expression levels were correlated with lymph node status and TNM stage. In TNBC cells, the ectopic expression of miR-135b promoted cell proliferation and invasion in vitro. In addition, our study proved that the overexpression of miR-135b significantly suppressed APC expression by targeting the 3'-untranslated region of APC, whereas enhanced APC expression could partially abrogate the miR-135b-mediated promotion of carcinogenic traits in TNBC cells. Taken together, our study demonstrated that miR-135b expression promoted the proliferation and invasion of TNBC by downregulating APC expression, indicating that miR-135b may serve as a promising target for the treatment of TNBC patients.

Synergistic effect of berberine and HMQ1611 impairs cell proliferation and migration by regulating Wnt signaling pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a biologically complex disease. Combination chemotherapy is a good strategy after surgery treatment. In this study, we report that berberine combined with HMQ1611 (BCH) had a good synergistic effect on the HCC. Our findings concluded that BCH showed good inhibition on the HCC proliferation and colony formation, which attributed to cell cycle arrest by BCH at G1 phase through impairing the expression of cyclinD1, cyclinE, and cdc2 and downregulated the phosphorylation of Akt, mTOR, and ERK. Moreover, BCH negatively regulated Wnt signaling pathway by upregulating the Axin and inhibiting the nuclear translocation of β-catenin. BCH suppressed the phosphorylation of LRP5/6, GSK3β, the expression of Wnt5a, Frizzled8, CK1, and APC, as well as the nucleus protein included MMP2, MMP3, MMP9, and c-myc. The above data of Wnt signaling regulators contributed to inhibition by BCH on cell migration. In vivo studies, BCH significantly suppressed the growth of SMMC-7721 xenograft tumors through downregulating Ki67 and β-catenin, as well as upregulating Axin and p-β-catenin. In conclusion, the results revealed that BCH exhibited potential antitumor activities against human liver cancer in vitro and in vivo, and the potential mechanism underlying these activities depended on the inhibition of the Wnt/β-catenin signaling pathway.

Long noncoding RNA LSINCT5 acts as an oncogene via increasing EZH2-induced inhibition of APC expression in osteosarcoma

Long noncoding RNAs (lncRNAs) are recognized as a class of critical regulators in various tumors. Recently, lncRNA LSINCT5 has been reported to promote the progression of bladder cancer, ovarian cancer, gastric cancer, and breast cancer. However, the biological function of LSINCT5 remains elusive in osteosarcoma (OS). In our study, we found that LSINCT5 was significantly upregulated in OS tissues than in adjacent normal tissues. Additionally, the expression of LSINCT5 was inversely associated with the prognosis of patients with OS. LSINCT5 knockdown dramatically inhibited OS cell proliferation in vitro and tumor growth in vivo. Mechanistic exploration revealed that LSINCT5 interacted with EZH2 to suppress the expression of APC, a negative regulator of the Wnt/β-catenin pathway. Moreover, rescue assays suggested that LSINCT5 exerted oncogenic roles by partially inhibiting APC expression in OS. In summary, our study demonstrated that LSINCT5 was a promising candidate for OS prognosis and therapy.

Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts.

A localized transcriptome at the synapse facilitates synapse-, stimulus- and transcript-specific local protein synthesis in response to neuronal activity. While enzyme-mediated mRNA modifications are known to regulate cellular mRNA turnover, the role of these modifications in regulating synaptic RNA has not been studied. We established low-input m6A-sequencing of synaptosomal RNA to determine the chemically modified local transcriptome in healthy adult mouse forebrains and identified 4,469 selectively enriched m6A sites in 2,921 genes as the synaptic m6A epitranscriptome (SME). The SME is functionally enriched in synthesis and modulation of tripartite synapses and in pathways implicated in neurodevelopmental and neuropsychiatric diseases. Interrupting m6A-mediated regulation via knockdown of readers in hippocampal neurons altered expression of SME member Apc, resulting in synaptic dysfunction including immature spine morphology and dampened excitatory synaptic transmission concomitant with decreased clusters of postsynaptic density-95 (PSD-95) and decreased surface expression of AMPA receptor subunit GluA1. Our findings indicate that chemical modifications of synaptic mRNAs critically contribute to synaptic function.

Oncogenic Role of MiR-20b is Mediated by a Positive Feedback Loop of Wnt//β-Catenin Pathway in Non-Small Cell Lung Cancer

Background: MicroRNAs (miRNAs) are a kind of endogenous non-encoding single stranded RNA which is able to regulate genes expression by targeting the 3’-untranslated region (UTR) and play an important role in many biological and pathological processes, such as inflammation and cancer. Methods: The expression levels of miRNAs and its regulated genes were evaluated by qPCR and Western-blot analysis respectively. The proliferation of cells was calculated by growth curve and colony formation. The migration and invasion assay was determined by trans-well study. Mouse xenograft model was applied for in vivo study. Findings: In this study, we found that miR-20b significantly increased in human non-small cell lung cancer (NSCLC) cell lines and patients’ tissues, suggesting that it possesses a carcinogenic role in lung cancer. It promoted the proliferation, migration and invasion of NSCLC cells by targeting and down-regulating the expression of APC which is a negative regulator of the canonical Wnt signaling pathway. Specifically, as the downstream of miR-20b, the activation of Wnt signaling could increases the transcription of miR-20b. Therefore, miR-20b and canonical Wnt signaling were coupled through a feed-forward positive feedback loop, forming a biological regulatory circuit. Finally, in vivo study further demonstrated that the increase of miR-20b could promote the growth of cancer cells. Interpretation: Overall, our findings offered compelling evidence that miR-20b contributes to the development of NSCLC by inhibiting APC via the canonical Wnt signaling pathway. Funding: This work was supported by FDCT grants from the Science and Technology Development Fund of Macao (Project code: 082/2013/A3,082/2015/A3,0003/2018/A1,130/2017/A3 and 046/2016/A2). Declaration of Interests: There is no conflict of interests. Ethics Approval Statement: Animal studies were approved by the Ethical Committee of Macau University of Science and Technology.

Wnt/β-catenin signaling pathway is involved in regulating the migration by an effective natural compound brucine in LoVo cells

BackgroundColorectal cancer remains the third most common malignancies and migration is one of the main factors for its high mortality rate. Brucine, a natural plant alkaloid, has been proved to possess a variety of pharmacological functions including anti-tumor activities. PurposeThe aim of this study was to investigate the inhibitory effect of brucine on the colorectal cancer and the underlying mechanism. MethodsIn this study, colony formation assay and transwell assay were used to investigate the effect of brucine on LoVo cells viability and migration. Immunofluorescence assay, western blot assay and Gelatin zymography assay were used to study the mechanism of brucine. Xenograft model in nude mice was induced to investigate the in vivo effect of brucine on LoVo cells. ResultsBrucine could significantly decrease the viability, inhibit the colony formation and induce the apoptosis of LoVo cells. Brucine could also suppress the migration of LoVo cells in a dose-dependent manner. Western blot analysis elucidated that the inhibition of migration was associated with the decreasing expression of matrix metalloproteinases including MMP2, MMP3 and MMP9. Moreover, we found that treatment of brucine could downregulate the expression of Frizzled-8, Wnt5a, APC and GSNK1A1, and increase the expression of AXIN1. Meanwhile, brucine also decreased the phosphorylation level of LRP5/6 and GSK3β, and increased the level of p-β-catenin. Xenografted model in nude mice study also revealed that oral administration of brucine could inhibit the growth and migration of LoVo cells by activating the expression of AXIN1 and p-β-catenin. ConclusionBrucine could suppress the migration of the colorectal cancer in vitro and in vivo and the effect was associated with the inhibition of the Wnt/β-catenin signaling pathway.

Alterations of Tumor Suppressor Genes Expression in Colorectal Cancer: Their Impact on Progression and Prediction of Patients Outcome

Background: Deregulation of tumor suppressor genes as APC, DCC and SMAD2 are related to tumorgenesis thus we aimed to investigate their expression among colorectal cancer to validate their relation with clinicopathological factors and the clinical outcome for CRC patients.
 Materials and Methods: Formalin-fixed paraffin samples from 115 colorectal cancer were investigated for APC, DCC and SMAD2 gene expression using quantitative PCR (QPCR) and their levels were analyzed versus clinicopathological factors and the overall survival (OS) of colorectal cancer patients.
 Results: A significant relation was reported between DCC and SMAD2 gene expression with clinical stages as they reported decrease expression among those with stage III. The three investigated genes were decreased significantly with poor histological differentiation colorectal cancer patients. The correlations between the expressions of the investigated genes revealed a significant correlation between SMAD2 and APC as well as between SMAD2 and DCC. Moreover patients with mean levels below and equal their expression values showed a considerable difference with OS.
 Conclusion: Gene expression of tumor suppressor genes APC, DCC and SMAD2 were significantly related to differential grading and patient's outcome thus pointing out their potential role as predictive markers for prognosis of colorectal cancer.

Deregulation of E-cadherin, β-catenin, APC and Caveolin-1 expression occurs in canine prostate cancer and metastatic processes

Prostate cancer is a heterogeneous disease with high levels of clinical and gene heterogeneity, consequently offering several targets for therapy. Dogs with naturally occurring prostate cancer are useful models for molecular investigations and studying new treatment efficacy. Three genes and proteins associated with the WNT pathway (β-catenin, APC and E-cadherin) and Caveolin-1 (CAV-1) were evaluated in canine pre-neoplastic proliferative inflammatory atrophy (PIA), prostate cancer and metastatic disease. The APC gene methylation status was also investigated. As in human prostate cancer, cytoplasmic and nuclear β-catenin, which are fundamental for activating the canonical WNT pathway, were found in canine prostate cancer and metastasis. Membranous E-cadherin was also lost in these lesions, allowing cellular migration to the stroma and nuclear localization of β-catenin. In contrast to human prostate tumours, no APC downregulation or hypermethylation was found in canine prostate cancer. The CAV-1 gene and protein overexpression were found in canine prostate cancer, and as in humans, the highest levels were found in Gleason scores ≥8. In conclusion, as with human prostate cancer, β-catenin and E-cadherin in the WNT pathway, as well as Caveolin-1, are molecular drivers in canine prostate cancer. These findings provide additional evidence that dogs are useful models for studying new therapeutic targets in prostate cancer.

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting.

The acquisition of biallelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. APC encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor β-catenin; APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis, and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting β-catenin in the nucleus. APC also suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA. Mutations in APC are often frameshifts, insertions, or deletions that introduce premature stop codons and lead to the production of truncated APC proteins that lack its normal functions and possess tumorigenic properties. Therapeutic approaches in development for the treatment of APC-deficient tumors are focused on the inhibition of canonical WNT signaling, especially through targets downstream of APC in the pathway, or on the restoration of wild-type APC expression.

Syphacia muris infection in rats attenuates colorectal carcinogenesis through oxidative stress and gene expression alterations. Implications for modulatory effects by Bryostatin-1.

Accumulating evidence suggest that some infectious agents may interfere in the natural progression of neoplasia. This study examined the association between chronic infection with adult Syphacia muris parasites and 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis in rats. In addition, the conceivable therapeutic effect of Bryostatin-1, a potent extract of the marine Bryozoan, Bugulane ritina, was investigated against this combined effect.DMH administration has induced aberrant crypt foci (ACF), surrogate biomarkers for colorectal carcinogenesis, while the S. muris infection combined with DMH has significantly increased the total numbers of ACF. Nonetheless, treatment with Bryostatin-1 after infection has significantly reduced the ACF numbers particularly larger ones. This inhibition was concomitant with significant inhibition in the immunohistochemical levels of the ki67, Caspase-3 and IgM levels in colorectal epithelium, as well as serum levels of IgM and IgG. Additionally, treatment with Bryostatin-1 after S. muris + DMH has modulated enzymatic antioxidative markers levels of superoxide dismutase and catalase as well as the non-enzymatic antioxidant markers levels of reduced glutathione, lipid peroxidation, nitric oxide and total antioxidant capacity. Further, treatment with Bryostatin-1 has down-regulated the mRNA expression levels of COX-2 and APC genes in colorectal mucosa. In conclusion, infection with S. muris during colorectal carcinogenesis has significantly modulated the oxidative stress markers in the colorectum, while treatment with Bryostatin-1 has exerted significant curative potential. A mechanism could be explained that Bryostatin-1 treatment has reduced oxidative stress markers activities along with affecting host to parasite immunity possibly leading to changes in the COX-2 and APC expression, retarding cellular proliferation and subsequently reducing the colorectal carcinogenesis events.

Parkin protein expression and its impact on survival of patients with advanced colorectal cancer.

Objective:Features of colorectal cancer such as natural history, molecular, chromosomal, and epigenetic alterations have been well described. However, there is still a lack of accurate prognostic markers, which is evident by the lower overall survival rates of patients with advanced cancer. Although alterations in parkin protein expression have been described in colorectal cancer, the functional significance of this protein remains unknown. The present study aimed to investigate the involvement of parkin expression in colorectal adenocarcinoma development and progression by evaluating the association between its expression, clinicopathological parameters, and expression of known proteins involved in colorectal cancer.Methods:Tissue microarrays consisting of 73 tumor and 64 normal tissue samples were generated to examine parkin expression and localization by immunohistochemistry.Results:A positive correlation of parkin and APC expression was observed in the superficial, intermediate, and profound regions of all cases (ρ = 0.37; P = 0.001). Parkin expression was also significantly associated with tumors in men (P = 0.049), those of the mucinous subtype (P = 0.028), and of advanced stage (III + IV, P = 0.041). In addition, increased parkin expression was observed in the invasive front tumor region (P = 0.013). More importantly, a positive correlation was found between parkin expression and the overall survival of patients with advanced colorectal cancer (P = 0.019). Multivariate analysis showed that parkin expression was independent of any of the clinicopathological parameters evaluated in relation to patient survival. Conclusions:These results suggest that parkin expression status can be used as a potential independent prognostic marker of survival in advanced colorectal cancer.

Lnc SAMD5-AS1 as ceRNA Inhibit Proliferation of Diffuse Large B Cell Lymphoma via Wnt/β-Catenin Pathway by Sponging miR-135b-5p to Elevate Expression of APC

Lnc SAMD5-AS1 as ceRNA Inhibit Proliferation of Diffuse Large B Cell Lymphoma via Wnt/β-Catenin Pathway by Sponging miR-135b-5p to Elevate Expression of APC

Modulation of APC expression in hMSC during nomadic culture on heterogeneous field of elasticity

Modulation of APC expression in hMSC during nomadic culture on heterogeneous field of elasticity

Prognostic impact of changes in base excision repair machinery in sporadic colorectal cancer

Objectiveto evaluate the prognostic value of base excision repair proteins in sporadic colorectal cancer. MethodsPre-treatment tumor samples from 72 patients with sporadic colorectal adenocarcinoma were assessed for APC, MPG, Polβ, XRCC1 and Fen1 expression by immunohistochemistry. The associations of molecular data were analyzed in relation to clinical features and TNM staging as a prognosis predictor and disease-free survival. ResultsHigher levels of MPG, Polβ and XRCC1, but not Fen1, were associated with unfavorable pathological outcomes, such as poor cellular differentiation, advanced TNM stages, presence of lymphatic and perineural invasions and metastatic lymph nodes. MPG and Polβ overexpression were associated with right-sided CRC. However, only MPG high expression is associated with shorter disease-free survival in CRC patients. ConclusionsOur results suggest that increased expression of MPG, Polβ and XRCC1 are more likely to evolve to poor pathological outcomes, but only the elevated expression of MPG protein predicts recurrence. The BER proteins appear to be suitable candidates to refine the TNM current staging of colorectal cancer.

Thymine DNA Glycosylase (TDG) is involved in the pathogenesis of intestinal tumors with reduced APC expression.

Thymine DNA Glycosylase (TDG) is a base excision repair enzyme that acts as a thymine and uracil DNA N-glycosylase on G:T and G:U mismatches, thus protecting CpG sites in the genome from mutagenesis by deamination. In addition, TDG has an epigenomic function by removing the novel cytosine derivatives 5-formylcytosine and 5-carboxylcytosine (5caC) generated by Ten-Eleven Translocation (TET) enzymes during active DNA demethylation. We and others previously reported that TDG is essential for mammalian development. However, its involvement in tumor formation is unknown. To study the role of TDG in tumorigenesis, we analyzed the effects of its inactivation in a well-characterized model of tumor predisposition, the ApcMin mouse strain. Mice bearing a conditional Tdgflox allele were crossed with Fabpl::Cre transgenic mice, in the context of the ApcMin mutation, in order to inactivate Tdg in the small intestinal and colonic epithelium. We observed an approximately 2-fold increase in the number of small intestinal adenomas in the test Tdg-mutant ApcMin mice in comparison to control genotypes (p=0.0001). This increase occurred in female mice, and is similar to the known increase in intestinal adenoma formation due to oophorectomy. In the human colorectal cancer (CRC) TCGA database, the subset of patients with TDG and APC expression in the lowest quartile exhibits an excess of female cases. We conclude that TDG inactivation plays a role in intestinal tumorigenesis initiated by mutation/underexpression of APC. Our results also indicate that TDG may be involved in sex-specific protection from CRC.

The effects of cigarette smoke nanoparticles in the colorectal carcinogenesis of wistar rats

Smoking cigarette is one of risk factors for developing colorectal carcinoma. Various researches have been made to suppress the toxicity of cigarette smoke. One of such effort is to reduce the size of cigarette smoke particles using nano water solution containing aromatic groups and EDTA. This study aims to assess the effects of this cigarette smoke nanoparticle regarding colorectal carcinogenesis. The experimental study was carried out with sequential post test only control group design. Thirty Wistar rats were divided into 3 groups: exposure to cigarettes smoke, exposure to smoke of cigarettes containing nano water solution and control for 14 weeks and 28 weeks. Colorectal epithelial morphology was assessed on the histopathology examination, whereas the expression of APC, KRAS, MSH2, MLH1, and p53 was assessed on immunohistochemistry procedure. Our results showed that cigarette smoke nanoparticles had better effects regarding colorectal epithelial morphology, especially through the increased expression of APC.

Determination of Rate-Limiting Factor for Formation of Beta-Catenin Destruction Complexes Using Absolute Protein Quantification.

Wnt/β-catenin signaling plays important roles in both ontogenesis and development. In the absence of a Wnt stimulus, β-catenin is degraded by a multiprotein "destruction complex" that includes Axin, APC, GSK3B, and FBXW11. Although the key molecules required for transducing Wnt signals have been identified, a quantitative understanding of this pathway has been lacking. Here, we calculated the absolute number of β-catenin destruction complexes by absolute protein quantification using LC-MS/MS. Similar amounts of destruction complex-constituting proteins and β-catenin interacted, and the number of destruction complexes was calculated to be about 1468 molecules/cell. We demonstrated that the calculated number of destruction complexes was valid for control of the β-catenin destruction rate under steady-state conditions. Interestingly, APC had the minimum expression level among the destruction complex components at about 2233 molecules/cell, and this number approximately corresponded to the calculated number of destruction complexes. Decreased APC expression by siRNA transfection decreased the number of destruction complexes, resulting in β-catenin accumulation and stimulation of the transcriptional activity of T-cell factor. Taken together, our results suggest that the amount of APC expression is the rate-limiting factor for the constitution of β-catenin destruction complexes.

Abstract B07: Loss of APC induces a dependence on elevated eIF2B5 function in colorectal cancer

Abstract Colorectal cancer (CRC) is the most common gastrointestinal malignancy and one of the leading causes of cancer death worldwide. Truncating mutations of the tumor suppressor APC that lead to deregulated WNT signaling are driver mutations in CRC. APC and its downstream effector, β-catenin, are regarded as non-druggable, prompting the search for novel interactions essential for survival of cells that have lost APC function. Here, we have restored doxycycline-inducible expression of full-length APC (APC wt) in SW480 cells, which carry truncated APC (APC mut). To identify genes that are essential for viability of APC mut cells, we conducted an shRNA screen targeting 5,000 genes with 25,000 shRNAs. The best scoring differential hits were multiple shRNAs that target the translation initiation factor eIF2B5, a subunit of the guanidine exchange factor (GEF) for eIF2. Validation experiments demonstrate a strong synthetic lethal effect of eIF2B5 knockdown with APC truncation in SW480 cells that can be rescued by APC induction. There is a clear survival window, which we can visualize using several shRNA sequences with different knockdown efficiencies. We confirm previous observations that loss of APC function results in an increase of global protein synthesis. Loss of APC also strongly induces expression of eIF2B5 and other subunits of eIF2B. Knockdown of eIF2B5 reduces overall protein translation. Although eIF2 function and overall ribosomal assembly are compromised upon depletion of eIF2B5, MYC protein levels are strongly upregulated, arguing that MYC can be translated in an eIF2-independent manner. Apoptosis upon eIF2B5 knockdown strictly depends on MYC upregulation. APC mut cells also display higher basal levels of the unfolded protein response (UPR) markers CHOP and ATF4, which are both further enhanced by eIF2B5 depletion. The UPR branch reflected by CHOP induction may contribute to cell death in our system. In conclusion, our data demonstrate a dual regulatory mechanism in which loss of APC induces expression of both MYC and eIF2B5. Full eIF2 activity is required to restrict the pro-apoptotic activity of MYC in APC mut cells. Thus, interfering with eIF2B5 function as GEF or GDF may be a promising treatment strategy for cells with truncated APC. Citation Format: Stefanie Peter, Friedrich-Wilhelm Uthe, Martin Eilers, Christoph-Thomas Germer, Armin Wiegering. Loss of APC induces a dependence on elevated eIF2B5 function in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B07.

Cigarette Smoke Induces Colorectal Carcinogenesis in Wistar Rats by Decreasing The Expression of APC, MSH2 and MLH1

<p>Colorectal carcinogenesis induced by cigarette smoke requires at least 30-40 years. This long time duration causes an animal research conducted becomes relevant. This research was carried out to observe colorectal carcinogenesis due to cigarette smoke exposure in Wistar Rat. The observations focused on changes in epithelial morphology and expression of APC, MSH2 and MLH1. Twenty male Wistar rats inbreed strain were randomly allocated into control group and experimental group exposure to cigarettes smoke for 14 weeks and 28 weeks sequentially. Colorectal epithelial morphology was assessed on the histopathology examination, whereas the expression of APC, MSH2 and MLH1 was assessed on aspect of immunohistochemistry. The comparative analysis between the two groups was performed using non-parametric Mann-Whitney U test. Histology of colorectal epithelium showed pattern of colitis associated cancer that was significant both in 14 weeks and 28 weeks of treatment. This research indicated negative expression of APC, MSH2 and MLH1 in the colorectal cancer that were significant at 28 weeks of exposure. This research implies that chronic exposure to cigarette smoke can induce colitis associated colorectal cancer through decreased expression of APC, MSH2 and MLH1. </p>

A kinetic model to study the regulation of β-catenin, APC, and Axin in the human colonic crypt.

The Wnt/[Formula: see text]-catenin pathway plays a crucial role in stem cell renewal and differentiation in the normal human colonic crypt. The balance between [Formula: see text]-catenin and APC along the crypt axis determines its normal functionality. The mechanism that deregulates this balance may give insight into the initiation of colorectal cancer. This is significant because the spatial dysregulation of [Formula: see text]-catenin by the mutated tumor suppressor gene/protein APC in human colonic crypts is responsible for the initiation and growth of colorectal cancer. We consider a regulatory function that promotes APC synthesis within the cell and its effect on the accumulation of the Wnt target protein, [Formula: see text]-catenin. It is evident that an APC gradient exists along the crypt axis; however, the mechanism by which APC expression is regulated within the cell is not well known. We investigate the dynamics of an APC regulatory mechanism with an increased level of Axin at the subcellular level. Model output shows an increase of APC for a diminished Wnt signal, which explains the APC gradient along the crypt. We find that the dynamic interplay between [Formula: see text]-catenin, APC, and Axin produces oscillatory behavior, which is controlled by the Wnt stimulus. In the presence of reduced functional APC, the oscillations are amplified, which suggests that the cell remains in a more proliferative state for longer periods of time. Increased Axin levels (typical of mammalian cells) reduce oscillatory behavior and minimize the levels of [Formula: see text]-catenin within the cell while raising the levels of APC.