المؤلفون: Ninet Sinaii, Guru Sonpavde, Amin H Nassar, Min Yuen Teo, Andrea B Apolo, Jonathan E Rosenberg, Giovanni Maria Iannantuono, Elias B A Chandran, Saad O Atiq, Dilara Akbulut, Nicholas I Simon, Abdul Rouf Banday, Salah Boudjadi, Sandeep Gurram, Gisela Butera, Jonathan A Coleman

المصدر: BMJ Oncology, Vol 3, Iss 1 (2024)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Background Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a subset of cancers and have been shown to confer sensitivity to immune checkpoint inhibition (ICI); however, there is a lack of prospective data in urothelial carcinoma (UC).Methods and analysis We performed a systematic review to estimate the prevalence of dMMR and MSI-H in UC, including survival and clinical outcomes. We searched for studies published up to 26 October 2022 in major scientific databases. We screened 1745 studies and included 110. Meta-analyses were performed if the extracted data were suitable.Results The pooled weighted prevalences of dMMR in bladder cancer (BC) and upper tract UC (UTUC) were 2.30% (95% CI 1.12% to 4.65%) and 8.95% (95% CI 6.81% to 11.67%), respectively. The pooled weighted prevalences of MSI-H in BC and UTUC were 2.11% (95% CI 0.82% to 5.31%) and 8.36% (95% CI 5.50% to 12.53%), respectively. Comparing localised versus metastatic disease, the pooled weighted prevalences for MSI-H in BC were 5.26% (95% CI 0.86% to 26.12%) and 0.86% (95% CI 0.59% to 1.25%), respectively; and in UTUC, they were 18.04% (95% CI 13.36% to 23.91%) and 4.96% (95% CI 2.72% to 8.86%), respectively. Cumulatively, the response rate in dMMR/MSI-H metastatic UC treated with an ICI was 22/34 (64.7%) compared with 1/9 (11.1%) with chemotherapy.Conclusion Both dMMR and MSI-H occur more frequently in UTUC than in BC. In UC, MSI-H occurs more frequently in localised disease than in metastatic disease. These biomarkers may predict sensitivity to ICI in metastatic UC and resistance to cisplatin-based chemotherapy.

وصف الملف: electronic resource

العلاقة: https://bmjoncology.bmj.com/content/3/1/e000335.fullTest; https://doaj.org/toc/2752-7948Test

الوصول الحر: https://doaj.org/article/d3920c29bad4423893885de5201f3040Test

المؤلفون: Salah Boudjadi, Jean-François Beaulieu

المصدر: Bio-Protocol, Vol 7, Iss 6 (2017)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: In normal as in cancerous cells, gene expression is tightly regulated by transcription factors, which are responsible for up- or down-regulation of thousands of targets involved in different cell processes. Transcription factors can directly regulate the expression of genes by binding to specific DNA sequences known as response elements. Identification of these response elements is important to characterize targets of transcription factors in order to understand their contribution to gene regulation. Here, we describe In silico analysis coupled to selected mutagenesis and promoter gene reporter assay procedures to identify and analyze response elements in the proximal promoter sequence of genes.

وصف الملف: electronic resource

العلاقة: https://bio-protocol.org/en/bpdetail?id=2181&type=0Test; https://doaj.org/toc/2331-8325Test

الوصول الحر: https://doaj.org/article/e5cec6d18d044679bf5b511f547c1efbTest

المؤلفون: Blanche Sénicourt, Salah Boudjadi, Julie C Carrier, Jean-François Beaulieu

المصدر: Heliyon, Vol 2, Iss 5 (2016)

مصطلحات موضوعية: Biological sciences, Cell biology, Science (General), Q1-390, Social sciences (General), H1-99

الوصف: The Hedgehog (HH) signaling pathway is involved in the maintenance of numerous cell types both during development and in the adult. Often deregulated in cancers, its involvement in colorectal cancer has come into view during the last few years, although its role remains poorly defined. In most tissues, the HH pathway is highly connected to the primary cilium (PC), an organelle that recruits functional components and regulates the HH pathway. However, normal epithelial cells of the colon display an inactive HH pathway and lack a PC. In this study, we report the presence of the PC in adenocarcinoma cells of primary colorectal tumors at all stages. Using human colorectal cancer cell lines we found a clear correlation between the presence of the PC and the expression of the final HH effector, GLI1, and provide evidence of a functional link between the two by demonstrating the recruitment of the SMO receptor to the membrane of the primary cilium. We conclude that the primary cilium directly participates in the HH pathway in colorectal cancer cells.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2405844016300299Test; https://doaj.org/toc/2405-8440Test

الوصول الحر: https://doaj.org/article/1b2713d2e845413c9950782f40d52a5aTest

المؤلفون: Jean-François Groulx, Salah Boudjadi, Jean-François Beaulieu

المصدر: Cancers, Vol 10, Iss 2, p 42 (2018)

مصطلحات موضوعية: colorectal cancer, MYC, integrin α6β4, ITGA6, alternative splicing, ESRP2, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: The α6 integrin subunit (ITGA6) pre-mRNA undergoes alternative splicing to form two splicing variants, named ITGA6A and ITGA6B. In primary human colorectal cancer cells, the levels of both ITGA6 and β4 integrin subunit (ITGB4) subunits of the α6β4 integrin are increased. We previously found that the upregulation of ITGA6 is a direct consequence of the increase of the pro-proliferative ITGA6A variant. However, the mechanisms that control ITGA6 expression and splicing into the ITGA6A variant over ITGA6B in colorectal cancer cells remain poorly understood. Here, we show that the promoter activity of the ITGA6 gene is regulated by MYC. Pharmacological inhibition of MYC activity with the MYC inhibitor (MYCi) 10058-F4 or knockdown of MYC expression by short hairpin RNA (shRNA) both lead to a decrease in ITGA6 and ITGA6A levels in colorectal cancer cells, while overexpression of MYC enhances ITGA6 promoter activity. We also found that MYC inhibition decreases the epithelial splicing regulatory protein 2 (ESRP2) splicing factor at both the mRNA and protein levels. Chromatin immunoprecipitation revealed that the proximal promoter sequences of ITGA6 and ESRP2 were occupied by MYC and actively transcribed in colorectal cancer cells. Furthermore, expression studies in primary colorectal tumors and corresponding resection margins confirmed that the up-regulation of the ITGA6A subunit can be correlated with the increase in MYC and ESRP2. Taken together, our results demonstrate that the proto-oncogene MYC can regulate the promoter activation and splicing of the ITGA6 integrin gene through ESRP2 to favor the production of the pro-proliferative ITGA6A variant in colorectal cancer cells.

وصف الملف: electronic resource

العلاقة: http://www.mdpi.com/2072-6694/10/2/42Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/768aba671ddb4c78964757d790c94133Test

المؤلفون: Salah Boudjadi, Gérald Bernatchez, Blanche Sénicourt, Marco Beauséjour, Pierre H. Vachon, Julie C. Carrier, Jean-François Beaulieu

المصدر: Cancers, Vol 9, Iss 8, p 96 (2017)

مصطلحات موضوعية: ITGA1, integrin α1, proliferation, survival, colorectal cancer, cell migration, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Integrins are a family of heterodimeric glycoproteins involved in bidirectional cell signaling that participate in the regulation of cell shape, adhesion, migration, survival and proliferation. The integrin α1β1 is known to be involved in RAS/ERK proliferative pathway activation and plays an important role in fibroblast proliferation. In the small intestine, the integrin α1 subunit is present in the crypt proliferative compartment and absent in the villus. We have recently shown that the integrin α1 protein and transcript (ITGA1) are present in a large proportion of colorectal cancers (CRC) and that their expression is controlled by the MYC oncogenic factor. Considering that α1 subunit/ITGA1 expression is correlated with MYC in more than 70% of colon adenocarcinomas, we postulated that the integrin α1β1 has a pro-tumoral contribution to CRC. In HT29, T84 and SW480 CRC cells, α1 subunit/ITGA1 knockdown resulted in a reduction of cell proliferation associated with an impaired resistance to anoikis and an altered cell migration in HT29 and T84 cells. Moreover, tumor development in xenografts was reduced in HT29 and T84 sh-ITGA1 cells, associated with extensive necrosis, a low mitotic index and a reduced number of blood vessels. Our results show that α1β1 is involved in tumor cell proliferation, survival and migration. This finding suggests that α1β1 contributes to CRC progression.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/9/8/96Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/779bb7ad92784c5c9d499f5730c8ad97Test

المؤلفون: Frederic G. Barr, Wenyue Sun, Thanh Hung Nguyen, Bishwanath Chatterjee, Puspa Raj Pandey, Salah Boudjadi

الوصف: Targeted monotherapies usually fail due to development of resistance by a subgroup of cells that evolve into recurrent tumors. Alveolar rhabdomyosarcoma is an aggressive myogenic soft-tissue cancer that is associated with a characteristic PAX3-FOXO1 gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1–induced rhabdomyosarcoma, deinduction of PAX3-FOXO1 simulates a targeted therapy that antagonizes the fusion oncoprotein. This simulated therapy results initially in regression of the primary tumors, but PAX3-FOXO1–independent recurrent tumors eventually form after a delay. We report here that upregulation of FGF8, a direct transcriptional target of PAX3-FOXO1, is a mechanism responsible for PAX3-FOXO1–independent tumor recurrence. As a transcriptional target of PAX3-FOXO1, FGF8 promoted oncogenic activity in PAX3-FOXO1–expressing primary tumors that developed in the myoblast system. In the recurrent tumors forming after PAX3-FOXO1 deinduction, FGF8 expression was necessary and sufficient to induce PAX3-FOXO1–independent tumor growth through an autocrine mechanism. FGF8 was also expressed in human PAX3-FOXO1–expressing rhabdomyosarcoma cell lines and contributed to proliferation and transformation. In a human rhabdomyosarcoma cell line with reduced PAX3-FOXO1 expression, FGF8 upregulation rescued oncogenicity and simulated recurrence after PAX3-FOXO1–targeted therapy. We propose that deregulated expression of a PAX3-FOXO1 transcriptional target can generate resistance to therapy directed against this oncogenic transcription factor and postulate that this resistance mechanism may ultimately be countered by therapeutic approaches that antagonize the corresponding downstream pathways.Significance:In a model of cancer initiated by a fusion transcription factor, constitutive activation of a downstream transcriptional target leads to fusion oncoprotein-independent recurrences, thereby highlighting a novel progression mechanism and therapeutic target.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8450126b3aa8b4de3966b0ea816161d0Test
https://doi.org/10.1158/0008-5472.c.6513652Test

المؤلفون: Frederic G. Barr, Wenyue Sun, Thanh Hung Nguyen, Bishwanath Chatterjee, Puspa Raj Pandey, Salah Boudjadi

الوصف: The Supplementary Table 1 includes the number of Upregulated and downregulated genes in the different groups of cell lines.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::093ad8fb7d4e4f33337e3b52cc11986fTest
https://doi.org/10.1158/0008-5472.22430587.v1Test

المؤلفون: Frederic G. Barr, Wenyue Sun, Thanh Hung Nguyen, Bishwanath Chatterjee, Puspa Raj Pandey, Salah Boudjadi

الوصف: This file contains Supplementary figures 1 to 6

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6475ee2f6a06889ad4dc31e7cfd627a4Test
https://doi.org/10.1158/0008-5472.22430593.v1Test

المؤلفون: Frederic G. Barr, Wenyue Sun, Thanh Hung Nguyen, Bishwanath Chatterjee, Puspa Raj Pandey, Salah Boudjadi

الوصف: The File includes the legends of the supplementary figures and supplementary table 1

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::842cd0b3a4df4c99be6cb3bd26d4e09aTest
https://doi.org/10.1158/0008-5472.22430590Test

المؤلفون: Bishwanath Chatterjee, Salah Boudjadi, Puspa Raj Pandey, Hana Kim, Wenyue Sun, Frederic G. Barr

المصدر: Cancer Research. 83:3536-3536

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Fusion-positive rhabdomyosarcoma (FP RMS) is an aggressive pediatric malignancy characterized by the presence of a PAX3-FOXO1 (P3F) or PAX7-FOXO1 fusion gene. Previous RNA expression studies have shown that these FP RMS tumors also express high levels of MYCN and lower levels of MYC. Our recent studies of FP RMS tumors revealed an inverse relationship between MYCN and MYC RNA expression in FP RMS tumors. Western blot studies of FP RMS cell lines and patient-derived xenograft (PDX) tumors identified tumors with high level MYCN and MYC protein expression as well as tumors with high level protein expression of either MYC or MYCN. To model the interaction of P3F with Myc family proteins in FP RMS, we generated human Dbt myoblasts with doxycycline-inducible P3F (iP3F) with or without constitutively expressed MYCN. We previously observed that doxycycline-treated human Dbt myoblasts engineered with iP3F and constitutive MYCN expression (Dbt-MYCN-iP3F) form foci in vitro and rapidly form tumors in vivo, while doxycycline-treated Dbt myoblasts engineered with only iP3F expression (Dbt-iP3F) do not form foci in vitro and form tumors in vivo at a slower rate. Western blot and qRT-PCR analysis of the parental and tumor-derived (TD) Dbt-MYCN-iP3F lines revealed high MYCN and low MYC expression. In contrast, Dbt-iP3F parental lines express moderate levels of MYC and very low levels of MYCN whereas iP3F TD lines show increased MYC and MYCN expression, though this level of MYCN expression is considerably less than that seen in Dbt-MYCN-iP3F lines. Using CRISPR-Cas9 technology to knockdown MYCN or MYC, we found a primary dependence on MYCN in both Dbt-MYCN-iP3F parental and TD lines as indicated by loss of focus formation following MYCN knockdown while MYC knockdown does not interfere with oncogenicity. In contrast, oncogenicity in Dbt-iP3F TD lines is primarily dependent upon MYC whereas MYCN knockdown results in a modest and variable effect on oncogenicity. To elucidate the role of Myc proteins on the expression of P3F target genes, we measured expression of several transcriptional targets in these parental and TD lines by RNA sequencing and qRT-PCR. Several target genes (such as FGFR4) showed comparable upregulation by P3F in both parental and TD lines with or without constitutive MYCN expression. In contrast, a few target genes (such as FGF8) were stimulated by P3F at low levels in Dbt-iP3F parental lines and were stimulated at much higher levels in Dbt-iP3F TD lines as well as in both Dbt-MYCN-iP3F parental and TD lines. This finding indicates that some P3F target genes do not require high MYCN or MYC expression whereas other P3F target genes can only be maximally stimulated by P3F in the presence of high levels of MYCN and/or MYC. We postulate that the dependence of FP RMS on high level expression of a Myc family protein may be explained by the need to stimulate expression of one or more of the P3F target genes in this latter category. Citation Format: Bishwanath Chatterjee, Salah Boudjadi, Puspa Raj Pandey, Hana Kim, Wenyue Sun, Frederic G. Barr. Role of Myc family proteins in fusion-positive rhabdomyosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3536.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::4bbfe60cd83a937f0b65b8de5f3d6d5dTest
https://doi.org/10.1158/1538-7445.am2023-3536Test