Integrin α6A splice variant regulates proliferation and the Wnt/β-catenin pathway in human colorectal cancer cells

Groulx, Jean-François; Giroux, Véronique; Beauséjour, Marco; Boudjadi, Salah; Basora, Nùria; Carrier, Julie; Beaulieu, Jean‐François

doi:10.1093/carcin/bgu006

Cited by 51 publications

(68 citation statements)

References 47 publications

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“…With such low levels of false positives combined with a sensitivity of 65% for both methods, ITGA6A appears to be an excellent candidate biomarker for inclusion in a multiplex stool RNA assay for CRC screening. It is interesting to note that the failure of ITGA6A to detect patients with Ad is consistent with our previous observation that ITGA6A is only significantly overexpressed in CRC lesions[26,27]. On the other hand, the areas under the ROC curves for ITGA6 determined by ddPCR and qPCR were 0.91 for Ad and 0.89 and 0.90, respectively, for CRC, confirming our previous findings on the usefulness of ITGA6 in the detection of colorectal lesions in a non-invasive assay.…”

Section: Discussionsupporting

confidence: 90%

Droplet digital PCR for quantification ofITGA6in a stool mRNA assay for the detection of colorectal cancers

Herring

Kanaoka

Tremblay

et al. 2017

WJG

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AIMTo investigate the use of droplet digital polymerase chain reaction (ddPCR) for detecting host mRNA markers in stools as a non-invasive test for colorectal cancer screening.METHODSddPCR and quantitative PCR were compared side by side for their performance in the detection of ITGA6 and ITGA6A transcripts in stool samples obtained from patients with various types of colorectal lesions (advanced adenomas and stage II-IV colorectal cancers) and control (patients displaying no pathological findings) using duplex TaqMan reactions for both methods. ITGA6 and ITGA6A were chosen for this proof-of-concept study based on their relative medium and low abundance in stool samples, respectively, as established in a previous study.RESULTSWe found that the ddPCR and qPCR methods performed equally well in this TaqMan duplex assay for the detection of ITGA6 and ITGA6A transcripts in stools of patients with colorectal lesions. For ITGA6, receiver operating characteristic (ROC) curve analysis showed comparable areas under the curve of 0.91 (P < 0.0001) and 0.89-0.90 (P < 0.0001) for the prediction of advanced adenomas and colorectal cancers, respectively. ITGA6A, which was detected at very low levels in control patients, was found to be significantly elevated (over 40 times) in stage II and III colorectal cancers (P < 0.0002). Comparison of the two sets of data revealed a strong correlation of the copy numbers obtained by ddPCR and qPCR for both ITGA6 and ITGA6A.CONCLUSIONWe found that ITGA6 and ITGA6A detection in stools of patients with colorectal cancers with ddPCR is comparable to that of qPCR using TaqMan assays.

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Section: Discussionsupporting

confidence: 90%

Droplet digital PCR for quantification ofITGA6in a stool mRNA assay for the detection of colorectal cancers

Herring

Kanaoka

Tremblay

et al. 2017

WJG

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“…Several integrins have previously been found to stimulate TGF‐β signaling by activating latent TGF‐β bound to the extracellular matrix . In addition, cooperative signaling between the Wnt and integrin pathways has been shown to contribute to cancer development and metastasis . Therefore, the inhibitory action of CD82 on the TGF‐β 1 and Wnt signaling may perhaps originate in its function of repressing the integrin signaling events that have positive crosstalk with the TGF‐β 1 /Smad and Wnt/β‐catenin pathways.…”

Section: Discussionmentioning

confidence: 99%

The metastasis suppressor CD82/KAI1 represses the TGF‐β₁ and Wnt signalings inducing epithelial‐to‐mesenchymal transition linked to invasiveness of prostate cancer cells

Lee

Kim

et al. 2019

The Prostate

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Background The epithelial‐to‐mesenchymal transition (EMT) is closely associated with cancer invasion and metastasis. Since the transforming growth factor β (TGF‐β) and Wnt signals induce EMT in various epithelial cell types, we examined whether and how the CD82/KAI1 metastasis suppressor affects the TGF‐β and Wnt signal‐dependent EMT in human prostate cancer cells. Methods The invasiveness of cancer cells was evaluated by examining their ability to pass through the basement membrane matrigel. The subcellular localizations of Smad4 and β‐catenin proteins were respectively examined by confocal microscopy following immunofluorescence antibody staining and immunoblotting analysis following subcellular fractionation. The transcriptional activities of the TGF‐β1‐responsive TRE and Wnt‐responsive Tcf/Lef promoters were determined by a luciferase reporter assay following transfection of the recombinant reporter vector into the cell. Results TGF‐β1 and Wnt3a treatments of human prostate cancer cells without CD82 expression resulted in not only increased invasiveness but also EMT involving the development of motile structures, downregulation of E‐cadherin, and upregulation of the mesenchymal proteins. However, in the cells with high levels of CD82, the TGF‐β1 and Wnt3a stimulations neither elevated invasiveness nor induced EMT. Furthermore, the TGF‐β1 signaling events occurring in the CD82‐deficient cells, such as phosphorylation of Smad2, nuclear translocation of Smad4, and transactivation of the TRE promoter, did not take place in the high CD82‐expressing cells. Further, high CD82 expression interfered with the Wnt signal‐dependent alterations in the phosphorylation pattern of glycogen synthase kinase 3β (GSK‐3β) in prostate cancer cells, which allowed GSK‐3β to continue phosphorylating β‐catenin, thereby attenuating the Wnt signaling effects on the nuclear translocation of β‐catenin and subsequent transactivation of the Tcf/Lef promoter. Conclusions The results of the present study suggest that CD82/KAI1 functions in suppressing TGF‐β1‐ and Wnt‐induced EMT in prostate cancer cells by inhibiting the TGF‐β1/Smad and Wnt/β‐catenin pathways. Therefore, loss or decrease of CD82 expression is likely to render prostate cancer cells prone to respond to the TGF‐β1 and Wnt signals with EMT, resulting in the development of a motile and invasive mesenchymal phenotype related to the initiation of the metastatic cascade.

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“…ITGB1 (also known as CD29), is predominantly expressed in tumor cells and its overexpression has been observed in several cancer types. 22,33,34 Moreover, ITGA6 has also been shown to be upregulated in >80% of CRC patients at the transcript level 35,36 and is known to dimerize with ITGB1, and subsequently bind to laminin. 37 By directly binding to the 3 0 UTRs of ITGA6 and ITGB1, we found miR-30e-5p to suppress mainly the adhesion of ITGA6 in CRC cells to laminin.…”

Section: Discussionmentioning

confidence: 99%

P53‐induced miR‐30e‐5p inhibits colorectal cancer invasion and metastasis by targeting ITGA6 and ITGB1

Laudato

Patil

Abba

et al. 2017

Intl Journal of Cancer

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The tumor suppressor P53 is a critical regulator of normal cellular homeostasis whose function is either distorted or lost in several cancer types including colorectal cancer (CRC). A small group of microRNAs have come to be recognized as essential mediators of P53 function. In a genome-wide systematic approach, we explored miRNAs that are substantially altered by P53 loss and found miR-30e to be the most significantly deregulated miRNA in P53-knockout human CRC cells. We identified miR-30e-5p to be a novel direct transcriptional target of P53 with gain and loss of function experiments revealing miR-30e-5p to be a significant regulator of tumor cell migration, invasion and in vivo metastasis mediated in part by integrins alpha-6 and beta-1 as novel targets. MiR-30e-5p also significantly reduced tumor cell proliferation by causing G1/S cell cycle arrest, which was achieved by inducing P21 and P27 expression. Finally, we found miR-30e-5p to be lost in resected CRC tumors as compared to normal colon tissues. Taken together, miR-30e-5p is a novel effector of P53-induced suppression of migration, invasion and metastasis.

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Integrin α6A splice variant regulates proliferation and the Wnt/β-catenin pathway in human colorectal cancer cells

Abstract: SummaryIntegrin α6Aβ4 is up-regulated in colorectal cancers. Knockdown of α6A in adenocarcinoma cell lines revealed a sustained reduction of cell growth both in cellulo and in xenografts as well as a repression of a number of Wnt/β-catenin pathway end points.

Cited by 51 publications

References 47 publications

Droplet digital PCR for quantification ofITGA6in a stool mRNA assay for the detection of colorectal cancers

Droplet digital PCR for quantification ofITGA6in a stool mRNA assay for the detection of colorectal cancers

The metastasis suppressor CD82/KAI1 represses the TGF‐β₁ and Wnt signalings inducing epithelial‐to‐mesenchymal transition linked to invasiveness of prostate cancer cells

P53‐induced miR‐30e‐5p inhibits colorectal cancer invasion and metastasis by targeting ITGA6 and ITGB1

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Integrin α6A splice variant regulates proliferation and the Wnt/β-catenin pathway in human colorectal cancer cells

Abstract: SummaryIntegrin α6Aβ4 is up-regulated in colorectal cancers. Knockdown of α6A in adenocarcinoma cell lines revealed a sustained reduction of cell growth both in cellulo and in xenografts as well as a repression of a number of Wnt/β-catenin pathway end points.

Cited by 51 publications

References 47 publications

Droplet digital PCR for quantification ofITGA6in a stool mRNA assay for the detection of colorectal cancers

Droplet digital PCR for quantification ofITGA6in a stool mRNA assay for the detection of colorectal cancers

The metastasis suppressor CD82/KAI1 represses the TGF‐β1 and Wnt signalings inducing epithelial‐to‐mesenchymal transition linked to invasiveness of prostate cancer cells

P53‐induced miR‐30e‐5p inhibits colorectal cancer invasion and metastasis by targeting ITGA6 and ITGB1

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The metastasis suppressor CD82/KAI1 represses the TGF‐β₁ and Wnt signalings inducing epithelial‐to‐mesenchymal transition linked to invasiveness of prostate cancer cells