Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression

Martínez-Ciarpaglini, Carolina; Oltra, Silvestre; Roselló, Susana; Roda, Desamparados; Mongort, Cristina; Carrasco, Francisca; González, José; Santonja, Francisco-José; Tarazona, Noelia; Huerta, Marisol; Espí, Alejandro; Ribas, Gloría; Ferrández, Antonio; Navarro, Samuel; Cervantes, Andrés

doi:10.1038/s41379-018-0124-5

Cited by 36 publications

(36 citation statements)

References 39 publications

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“…Tumor budding has been linked to EMT and CRCs with high budding at the invasive margin contain tumor cells that overexpress EMT-related genes, such as ZEB1, ZEB2, DES, TGFb3, and VIM, involved in cell migration and extracellular matrix remodeling. 25,26 We found that high tumor budding was significantly less common in dMMR versus pMMR cancers. An association between a higher number of tumor buds and the mesenchymal subtype (CMS4) of CRC has been documented using transcriptomic-based tumor profiling.…”

Section: Annals Of Oncologymentioning

confidence: 85%

Analysis of tumor microenvironmental features to refine prognosis by T, N risk group in patients with stage III colon cancer (NCCTG N0147) (Alliance)

et al. 2020

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Background: Tumor-infiltrating lymphocytes (TILs), tumor budding, and micropapillary architecture may influence tumor growth and metastatic potential, thereby enhancing prognostic stratification. We analyzed these features and their relative contribution to overall outcome and in low (T1e3 N1) and high (T4 and/or N2) risk groups that are used to inform the duration of adjuvant chemotherapy in patients with resected stage III colon cancers. Patients and methods: Among 1532 patients treated in a phase III adjuvant trial of FOLFOX-based therapy, intraepithelial TIL densities, tumor budding, and micropapillary features were analyzed and quantified in routine histopathological sections with light microscopy. Optimal cut-points were determined in association with diseasefree survival (DFS) in training and validation sets. Associations or relative contributions of individual features or combined variables with DFS were determined using multivariable Cox regression models. Results: TILs, tumor budding, and micropapillary features were shown to differ significantly by T, N risk groups and by mismatch repair (MMR) status. Low TILs, high budding, and their combined variable [hazard ratio ¼ 2.07 (95% CI, 1.50% to 2.88%); P adj < 0.0001], but not micropapillary features, were each significantly associated with poorer DFS in a training data set and confirmed in a validation set. TILs were prognostic in proficient mismatch repair (pMMR) and deficient mismatch repair (dMMR) tumors; budding was prognostic only in pMMR tumors. The percentage relative contribution of budding/TILs to DFS was second only to nodal status overall, was second (24.4%) after KRAS in lowrisk patients, and was the most important contributor (45.4%) in high-risk patients. Conclusions: TIL density and tumor budding were each validated as significant prognostic variables and their combined variable provided robust prognostic stratification by T, N risk groups, being the strongest predictor of DFS among highrisk stage III patients. ClinicalTrials.gov Identifier: NCT00079274.

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Section: Annals Of Oncologymentioning

confidence: 85%

Analysis of tumor microenvironmental features to refine prognosis by T, N risk group in patients with stage III colon cancer (NCCTG N0147) (Alliance)

et al. 2020

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“…IHC assays were performed in the 36 CRC patients as we previously described . The primary antibodies used were MLH1 (clone IR079, dilution 1:100; Dako), MSH2 (clone IR085, dilution 1:100; Dako), PMS2 (clone IR087, dilution 1:100; Dako), and MSH6 (clone IR086, dilution 1:100; Dako).…”

Section: Methodsmentioning

confidence: 99%

Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy

et al. 2019

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Somatic mutation analysis and evaluation of microsatellite instability (MSI) have become mandatory for selecting personalized therapy strategies for advanced colorectal cancer and are not available as routine methods in Paraguay. The aims of this study were to analyze the molecular profile as well as the microsatellite status in a series of advanced colorectal patients from two public hospitals from Paraguay, to introduce these methodologies in the routine practice to guide the therapeutic decisions. Thirty‐six patients diagnosed with advanced colorectal cancer from two referent public hospitals from Paraguay were recruited from May 2017 to February 2018. Sequenom Mass spectrometry, Oncocarta Panel V.1 was applied to analyze the mutational profile from formalin‐fixed paraffin‐embedded samples. The microsatellite status was tested by immunohistochemistry (IHC). The mean age of the patients was 52 years with a range from 20 to 74 years. Eighty‐three percent of the patients included in the study have advanced‐stage tumors at the moment of the diagnosis. Sixteen patients (44.4%) were wild‐type for all the oncogene regions analyzed with the Oncocarta panel. Thirty‐two hot‐spot pathogenic variants on seven oncogenes, among 20 patients (55.6%), were identified, including KRAS, NRAS, BRAF, PI3KCA, FGFR, epidermal growth factor receptor, and PDGFRA. Moreover, 14 (38.8%) of these patients presented pathogenic variants in KRAS/NRAS or BRAF genes that have implications in the clinical practice decisions. Five patients (14%) presented MSI. The IHC study for microsatellite status and the molecular profile analysis through Sequenom mass spectrometry are feasible and useful methods, due to identify those patient candidates for targeted therapies and for the budgetary calculations of the National Health Plans.

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“…9,10 Among them, there are many studies on miR-200c and colon cancer, and it has been shown that low expression of miR-200c is associated with poor prognosis of patients. [11][12][13] However, the regulation of colon cancer metastasis by miR-200c is a complex biological network. Therefore, the regulatory mechanism of miR-200c on colon cancer metastasis deserves further study.…”

Section: Introductionmentioning

confidence: 99%

miR-200c /FUT4 axis prevents the migration, invasion and proliferation of colon cancer cells by downregulating Wnt/β-catenin pathway

Cong

Yang

Xia

et al. 2020

Preprint

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Background To investigate the effects of miR-200c targeting fucosyltransferase 4 (FUT4) on the proliferation, migration and invasion of colon cancer cells and further to explore its mechanism. Methods The expression of miR-200c and FUT4 mRNA in Lovo and SW480 cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR), and their correlation was analyzed by Pearson. LipofectamineTM 2000 transfection reagent was used to transfect miR-200c mimic, FUT4 siRNA, FUT4 mimic and FUT4 mimic negative control into Lovo and SW480 cells, and RT-PCR was used to analyze the effect of transfection. Cell counting kitcck-8 (CCK-8), cloning and transwell assays were used to detect the migration, invasion and proliferation of Lovo and SW480 cells, respectively. Immunofluorescence was used to analyze the expression of Ki-67 protein. Moreover, the expression of Wnt/β-catenin signaling pathway-related proteins were detected by western blot. Double luciferase experiment was performed to verify the targeting relationship between miR-200c and FUT4. Results Pearson results showed that miR-200c and FUT4 were negatively correlated in Lovo and SW480 cells (correlation coefficients were − 0.9046 and − 0.9236, respectively). MiR-200c overexpression inhibits the proliferation, migration and invasion of Lovo cells by down-regulating FUT4. The expression of Ki67 positive cells and Wnt/β-catenin signaling pathway-related proteins were reduced in miR-200c overexpression and FUT4 silencing groups. The scientific search and dual luciferase reporting system identified FUT4 was the target of miR-200c. Conclusion In conclusion, miR-200c overexpression inhibits FUT4 expression and down-regulates the Wnt/β-catenin signaling pathway, thereby inhibiting the migration, invasion and proliferation of colon cancer cells.

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Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression

Cited by 36 publications

References 39 publications

Analysis of tumor microenvironmental features to refine prognosis by T, N risk group in patients with stage III colon cancer (NCCTG N0147) (Alliance)

Analysis of tumor microenvironmental features to refine prognosis by T, N risk group in patients with stage III colon cancer (NCCTG N0147) (Alliance)

Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy

miR-200c /FUT4 axis prevents the migration, invasion and proliferation of colon cancer cells by downregulating Wnt/β-catenin pathway

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