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Axin1 deficiency does not impair intestinal differentiation in mouse small intestine and colon. (A) Villin, Alcian blue, lysozyme, and chromogranin B staining of representative intestinal sections from WT (Axin1 fl/fl or Vil CreER T2 ;Axin1 þ/þ ) and KO (Axin1 DIEC ) mice. The mice were killed on day 5, after 4 days of tamoxifen injections. Hematoxylin and fast red were used as a nuclear counterstain for villin, lysozyme, and chromogranin B staining (scale bar: 50 mm), and for Alcian blue staining (scale bar: 100 mm), respectively. Scale bar: 100 mm. (B) Villin, Alcian blue, and chromogranin B staining of representative colon sections from WT (Axin1 fl/fl or Vil CreER T2 ;Axin1 þ/þ ) and KO (Axin1 DIEC ) mice. The mice were killed on day 5, after 4 days of tamoxifen injections. Hematoxylin and fast red were used as a nuclear counterstain for villin and chromogranin B staining (scale bar: 50 mm), and for Alcian blue staining (scale bar: 100 mm), respectively. Black arrowheads are chromogranin-positive cells.
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Background & Aims
Axin1 is a negative regulator of Wnt/β-catenin signaling with tumor suppressor function. The Wnt pathway has a critical role in the intestine, both during homeostasis and cancer, but the role of Axin1 remains elusive.
Methods
We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific Axin1-k...
Citations
... A comparative analysis of mutations in the members of the destruction complex across different tumors, as depicted in Fig. 7, highlights significant tissue-specific variations, particularly within complexes composed of AXIN1 or AXIN2. Notably, in the mouse small intestine and colon, AXIN1 deficiency does not impede intestinal differentiation, as AXIN2 can effectively compensate for the loss of AXIN1, leading to the downregulation of WNT/β-catenin activity [189]. However, the mutation data suggests that AXIN1 and CTNNB1 play more pivotal roles in the liver. ...
AXIN1, has been initially identified as a prominent antagonist within the WNT/β-catenin signaling pathway, and subsequently unveiled its integral involvement across a diverse spectrum of signaling cascades. These encompass the WNT/β-catenin, Hippo, TGFβ, AMPK, mTOR, MAPK, and antioxidant signaling pathways. The versatile engagement of AXIN1 underscores its pivotal role in the modulation of developmental biological signaling, maintenance of metabolic homeostasis, and coordination of cellular stress responses. The multifaceted functionalities of AXIN1 render it as a compelling candidate for targeted intervention in the realms of degenerative pathologies, systemic metabolic disorders, cancer therapeutics, and anti-aging strategies. This review provides an intricate exploration of the mechanisms governing mammalian AXIN1 gene expression and protein turnover since its initial discovery, while also elucidating its significance in the regulation of signaling pathways, tissue development, and carcinogenesis. Furthermore, we have introduced the innovative concept of the AXIN1-Associated Phosphokinase Complex (AAPC), where the scaffold protein AXIN1 assumes a pivotal role in orchestrating site-specific phosphorylation modifications through interactions with various phosphokinases and their respective substrates.
... 11 A study utilizing RNA-seq has unveiled that Axin1 is linked to IFN-γ/STAT1/Th1 immune program through an unidentified mechanism; moreover, CRC patients exhibiting an Axin1-dependent gene expression signature tend to have a more favorable prognosis. 4 Guo et al. propose that Axin1 enhances the antiviral response to influenza by activating the JNK/c-Jun and Smad3 pathways, reducing virus replication, and increasing interferon (IFN) production. Overexpressing Axin1 or using the Axin1 stabilizer XAV939 has been shown to decrease influenza virus replication in lung epithelial cells. ...
... The tissue-specific role of Axin1 in immunity is still unknown. A recent study reported that Axin1 stimulates intestinal inflammation via an interferon-gamma/Th1 program that prevents tumor growth 4 . Our paper has demonstrated that Axin1 and the microbiome are promising targets for colitis. ...
... Increased Wnt/β-catenin signaling and intestinal proliferation may be a contributing factor, and further investigations in the colon may elucidate this mechanism. Moreover, dissecting the colonic mechanisms of Axin1 may elucidate its role in intestinal homeostasis and colorectal cancer 4,27,28 . Microbiome and spatially resolved metabolomics analysis reveal the anticancer role of intestinal A. muciniphila by crosstalk with intratumoral microbiota and reprogramming tumoral metabolism in a lung cancer model 29 . ...
Classically, Axin1 is considered a regulator of Wnt/β-catenin signaling. However, Axin1’s roles in host-microbial interactions have been unknown. Our recent study has demonstrated that deletion of intestinal epithelial Axin1 in epithelial cells and Paneth cells protects the host against colitis by enhancing Akkermansia muciniphila. Loss of intestinal epithelial or Paneth cell Axin1 results in increased Wnt/β-catenin signaling, proliferation, and cell migration. This is associated with morphologically altered goblet and Paneth cells, including increased Muc2 and decreased lysozyme. Axin1 deletion specifically enriched Akkermansia muciniphila. Akkermansia muciniphila in Axin1 knockout mice is the driver of protection against DSS-induced inflammation. Here, we feature several significant conceptual changes, such as differences between Axin1 and Axin2, Axin1 in innate immunity and microbial homeostasis, and Axin1 reduction of Akkermansia muciniphila. We discuss an important trend in the field related to Paneth cells and tissue-specific Axin1 manipulation of microbiome in health and inflammation.
... Still, after the administration of the BMAP-27 peptide, a significant upregulation of p53 expression in the primary colon cancer cell line was observed. The development of colon cancer is closely linked to the inactivation of the AXIN1 gene (Sanson et al. 2023). ...
BMAP-27 peptide is reported to possess apoptotic and anti-proliferative effects against cancer cells but the actual mechanism of action is yet to be investigated. In the current investigation, we aimed to study the role of the BMAP-27 peptide in reducing proliferation and increasing apoptosis in colon cancer cell lines. In this study, we used primary and metastatic colon cancer cell lines SW480 and SW620. Cell proliferation was measured using MTT and CCK-8 assays, and cellular damage was analyzed by lactate dehydrogenase assay. Apoptosis, cell cycle, and proliferation potentials were measured by the expression of CASPASE3, BAX, BCL-2, TP53, CDK-6, PCNA, WNT11, AXIN1, and CTNNB1 genes. Additionally, in-silico studies were conducted to determine the binding affinities of BMAP-27 with adenomatous polyposis coli (APC) and β-catenin proteins, one of the primary regulators of colon cancer. BMAP-27 peptide reduced colon cancer cell proliferation, upregulated tumor suppressor genes CASPASE3, BAX, TP53, AXIN1 expression, and downregulated the expression of oncogenes BCL-2, CDK-6, PCNA, WNT11, CTNNB1 in both the cell lines, however, in the primary colon cancer cell line the changes are found to be more significant. The molecular dynamic simulation analysis revealed substantial binding affinity of the peptide to APC and β-catenin proteins. BMAP-27 peptide significantly inhibited the proliferation and induced apoptosis in the primary colon cancer cell line than in the metastatic colon cancer cell line. In-silico results suggest that BMAP-27 shows a strong binding affinity with APC and β-catenin proteins, highlighting its role in inhibiting colon cancer cell proliferation.
... To identify unique functions of Axin1, Sanson et al 5 initiated colonic tumors in mice using the mutagen azoxymethane (AOM), and then promoted tumorigenesis with the colon irritant dextran sodium sulfate (DSS). 5 Indeed, treated Axin1-knockout mice developed more adenocarcinomas than treated wild-type mice, indicating that Axin2 could not compensate for Axin1 in this tumorsuppressor context. Unexpectedly, the DSS-treated Axin1 knockout mice displayed less weight loss than treated wild-type mice (both with and without AOM), suggesting a novel proinflammatory role for Axin1. ...
... 6 In human colon cancers, the Axin1-deficient gene signature correlated with a small but significant decrease in disease-free survival. 5 Thus, colon cancers with an Axin1-proficient signature might respond favorably to combination therapy using Axin-stabilizing tankyrase inhibitors and immune checkpoint inhibitors. ...
... Overall, the study provides compelling evidence that Axin1 and Axin2 have overlapping functions in Wnt signaling, but unique functions in tumor suppression. 5 Moreover, the investigators uncovered a proinflammatory role for Axin1, beyond that of a Wnt signal regulator. Although the mechanistic details of this emerging new Axin1 function remain to be determined, Wnt-independent roles for Axin1 and other tumor suppressors could serve as innovative platforms for future ...
Casein kinase 1ε (CK1ε) and axis inhibitor 1 (AXIN1) are crucial components of the β‐catenin destruction complex in canonical Wnt signaling. CK1ε has been shown to interact with AXIN1, but its physiological function and role in tumorigenesis remain unknown. In this study, we found that CK1δ/ε inhibitors significantly enhanced AXIN1 protein level in colorectal cancer (CRC) cells through targeting CK1ε. Mechanistically, CK1ε promoted AXIN1 degradation by the ubiquitin–proteasome pathway by promoting the interaction of E3 ubiquitin‐protein ligase SIAH1 with AXIN1. Genetic or pharmacological inhibition of CK1ε and knockdown of SIAH1 downregulated the expression of Wnt/β‐catenin‐dependent genes, suppressed the viability of CRC cells, and restrained tumorigenesis and progression of CRC in vitro and in vivo . In summary, our results demonstrate that CK1ε exerted its oncogenic role in CRC occurrence and progression by regulating the stability of AXIN1. These findings reveal a novel mechanism by which CK1ε regulates the Wnt/β‐catenin signaling pathway and highlight the therapeutic potential of targeting the CK1ε/SIAH1 axis in CRC.
This study aimed to investigate the effects of nanoparticles on macrophage polarization and their subsequent influence on post-tumorigenic behavior. Initially, seven different nanoparticles were applied to macrophages, and Zn-Ni-FeO (100...
Introduction:
The dysregulation of the c-Jun NH2-terminal kinase (JNK) pathway has been increasingly reported in human malignancies. Aberrant expression of the JNK pathway has also been implicated in the progression of Esophageal Squamous Cell Carcinoma (ESCC). However, the specific role and regulatory mechanisms of JNK2 in ESCC have not been extensively investigated.
Method:
In this study, we examined JNK2 expression in patient samples and performed experiments involving the knockdown and inhibition of the JNK2 in ESCC cell lines.
Result:
Higher JNK2 expression was observed in tumor tissues compared to adjacent tissues. JNK2 overexpression was associated with advanced disease stages and poor prognosis. Furthermore, knockdown or inhibition of JNK2 in ESCC cell lines resulted in a decrease in cell proliferation and migration.
Conclusion:
Additionally, a significant decrease in the expression of β-catenin and vimentin, along with an increase in the expression of Axin2, was observed upon downregulation of JNK2. Our study provides insight into the role of JNK2 in ESCC and its potential regulatory mechanism, offering a potential therapeutic strategy for ESCC patients with aberrant JNK2 expression.
