Browsing by Subject "Colon cancer"
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- PublicationOpen AccessBATF is involved in the malignant phenotype and epithelial-mesenchymal transition of colon cancer cells via ERK/PD-L1 signaling(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Chen, Xiaoqiong; Dong, Huaqian; Jin, LipingObjective. Transcription factors have emerged as primary regulators in colon cancer. Basic Leucine Zipper Transcription Factor (BATF) was found to be differentially expressed in colon cancer. This study aimed to explore the impact of BATF on the malignant phenotype and epithelial-mesenchymal transition (EMT) process. Methods. Based on The Cancer Genome Atlas (TCGA) data, the correlation between BATF and patients’ overall prognosis was analyzed. BATF expression in epithelial and colon cancer cells was evaluated. By knocking down its levels in colon cancer cells, its effects on the malignant phenotype, apoptosis, EMT progression, and ERK/PD-L1 were evaluated. Cells were treated with ERK/PD-L1 agonists, and the BATF cell regulation was re-examined. Results. BATF levels were negatively correlated with patients’ overall survival. BATF is upregulated in colon cancer cell lines, and BATF knockdown in HCT116 cells suppressed the malignant cellular phenotypes (proliferation, migration, and invasion) and increased apoptosis. BATF knockdown inhibited EMT and ERK/PD-L1 signaling activation, whereas upon agonist treatment, BATF potency was disrupted. Conclusion. This study revealed that BATF is involved in the malignant phenotype and EMT of colon cancer cells, and this process may be mediated by ERK/PD-L1 signaling
- PublicationOpen AccessBeneficios del ejercicio y/o actividad física en los cinco tipos de cáncer con mayor incidencia y mortalidad a nivel mundial: Una revisión narrativa(Universidad de Murcia, Servicio de Publicaciones, 2023) Fuentes-Nuñez, Javier; Olivares-Gómez, Carelia; Farías-Valenzuela, Claudio; Poblete-Aro, Carlos; Alvarez-Arangua, Sebastián; Ferrero-Hernández, PalomaEsta revisión tiene como objetivo declarar los beneficios del ejercicio físico y/o la actividad física en los cinco tipos de cáncer con mayor tasa mortalidad en el mundo. Se realizó una búsqueda en las bases de datos: Pubmed, Cochrane, Scopus, Web of Science, Scielo (Latinoamérica) y Medline. Los términos usados para la búsqueda fueron: “cáncer de pulmón”, “cáncer de hígado”, “cáncer de mama”, “cáncer de estómago”, “cáncer de colon”, “ejercicio físico”, “actividad física”, “ejercicio de resistencia” y “ejercicio aeróbico”. El ejercicio físico y la actividad física han demostrado beneficios tanto en variables morfológicas, metabólicas y psicológicas, teniendo un impacto positivo en el aumento de la funcionalidad, esperanza de vida y calidad de vida en pacientes con cáncer. El ejercicio aeróbico demostró mayores beneficios en el consumo de oxígeno, además de una alta adherencia, mientras que el entrenamiento de fuerza en una mayor capacidad específicamente en los miembros inferiores.
- PublicationOpen AccessC-C motif chemokine ligand 14 inhibited colon cancer cell proliferation and invasion through suppressing M2 polarization of tumor-associated macrophages(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Li, Na; Liang, Xiao; Li, Jiawen; Li, Teng; Guo, ZuomingBackground. Colon cancer is one of the most common cancers with high incidence and high mortality. Chemokines play a crucial role in the development of cancer. Methods. Here, qRT-PCR was performed to detect gene expression. Western blot and immunohistochemistry were implemented to examine the expression of C-C motif chemokine ligand 14 (CCL14) in colon tumors. Besides, the expression of CD68 and CD206 in tumors was measured by immunohistochemistry. The percentages of M1- and M2-polarized macrophages were detected by flow cytometry. Furthermore, CCK-8 assay was performed to detect cell proliferation, and Transwell assay for cell invasion. Results. CCL14 was decreased in both colon tumors and colon cancer cells, and many tumor-associated macrophages (TAMs) infiltrated into the tumor. An increase CCL14 inhibited colon cancer cell proliferation. Importantly, CCL14 promoted THP-1 to M1 polarization induced by LPS and IFN-γ, and inhibited THP-1 to M2 polarization induced by IL-4 and IL-13. Besides, CCL14 enhanced the inhibition of M1-polarized macrophages to colon cancer cell proliferation and invasion, and reversed the promotion of M2-polarized macrophages to cell proliferation and invasion. Conclusion. Our data demonstrated that CCL14 inhibited the proliferation and invasion of colon cancer cells through suppressing the formation of M2-like TAMs
- PublicationOpen AccessCalcium, calcium-sensing receptor and growth control in the colonic mucosa(F. Hernández y J.F. Madrid. Murcia: Universidad de Murcia, Departamento de Biología Celular e Histología., 2011) Varani, JamesA role for calcium in epithelial growth control is well-established in the colon and other tissues. In the colon, Ca2+ “drives” the differentiation process. This results in sequestration of ß-catenin in the cell surface / cytoskeletal complex, leaving ß-catenin unavailable to serve as a growth-promoting transcription enhancer in the nucleus. The signaling events that lead from Ca2+ stimulation to differentiation are not fully understood. A critical role for the extracellular calcium-sensing receptor (CaSR) is assumed, based on CaSR localization to the differentiating epithelial cells in the normal colonic mucosa (upper half of the crypt and crypt surface), decreased CaSR expression in colon carcinoma, and the results from in vitro studies with colonic epithelial cell lines. While Ca2+ is well-accepted as a growth-regulating agent in the colon, suppression of cell proliferation is not complete. At least part of the reason for this is the inherent variability in Ca2+ responsiveness among individual epithelial cells. Of interest, colon epithelial cells that are resistant to the growth-regulating activity of Ca2+ alone are still responsive to Ca2+ in conjunction with other transition metals. Whether a multi-mineral approach will, ultimately, prove to be more effective than Ca2+ alone as a colon cancer chemopreventive agent remains to be seen, but certainly worth investigating.
- PublicationOpen AccessCancer stem cell markers CD44v9+/CD133- are associated with low apoptosis in both sporadic and ulcerative colitis-associated colorectal cancers(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2022) Nakagomi, Eriko; Mikami, Tetuo; Funahashi, Kimihiko; Okazumi, Shinichi; Shibuya, Kazutoshi; Hiruta, Nobuyuki; Igarashi, YoshinoriObjective. To elucidate tumor cell behavior associated with cancer stem cell (CSC) marker expression, the expression of CD133, CD44v9, and ALDH1A1, which are considered markers of CSCs, was examined in sporadic and ulcerative colitis (UC)- associated colorectal tumors. Methods. A total of 23 cases of sporadic colorectal cancer and 44 cases of adenoma were collected. Additionally, 22 cancer lesions and 38 dysplasia lesions were selected from 28 colectomy cases of UC with neoplastic lesions. Lesions were examined by immunohistochemistry using primary antibodies against CD133, CD44v9, ALDH1A1, Ki-67, cleaved-Caspase 3, and p53. Results. CD133, CD44v9, and ALDH1A1 showed higher expression in both sporadic and UC-associated tumors than in the normal mucosa. ALDH1A1 expression in sporadic cancer was higher in the right colon than in the left colon (p=0.0089). ALDH1A1 expression in UC-associated cancer was higher in those with longer disease duration than in those with shorter disease duration (p=0.019). The CD44v9+/CD133- region had fewer cleaved-Caspase 3 positive cells in both sporadic and UC-associated cancers. In sporadic cancer, CD133+/ALDH1A1+ regions had fewer apoptotic cells than CD133+/ALDH1A1- regions, while CD133+/ALDH1A1- regions were less proliferative than CD133+/ALDH1A1+ regions in UC-associated cancer. Conclusion. CD44+/CD133- regions were commonly associated with low apoptosis in sporadic and UC-associated cancers; thus, these were considered target areas for CSCs. Additionally, the combination of markers comprising CSCs may differ between sporadic and UC-associated cancers.
- PublicationOpen AccessExpression of TFF3 during multistep colon carcinogenesis(Murcia : F. Hernández, 2007) John, R.; El-Rouby, N.M.; Tomasetto, C.; Rio, M.C.; Karam, S.M.The pathogenesis of colon cancer is not well understood. This common type of cancer is generally believed to occur in a multistep process which involves alterations of various tumor suppressor genes and oncogenes during the progression through benign lesions towards carcinoma. TFF3 is a product of the colonic epithelium and has been implicated in colonic mucosal protection and also in the aggressiveness of colon cancer cells. The aim of this study was to analyze the expression of TFF3 during propagation towards cancer development in the human colon. Colonic tissues representing colitis, adenomatous polyposis, tubulovillous adenoma, and mucoid/adeno-carcinomas were processed for immunohistochemistry using an antibody specific for human TFF3. The results were correlated with those of PCNA-labeling, quantified, and compared with those of control tissues obtained from the safe margin of macroscopically normal colonic mucosa of patients with colon cancer. The data showed marked down-regulation of TFF3 expression in adenomatous polyposis, then TFF3 expression returns to about control level during adenoma and remains high during mucoidand adeno-carcinomas. Colonic tissues with highly invasive cancer cells were characterized by statistically significant down-regulation of TFF3 expression. The changes observed in expression of TFF3 showed an inverse correlation with cell proliferation and suggest that it might play a protective role against colon carcinogenesis. Key words:
- PublicationOpen AccessInhibition of ubiquitin specific peptidase 8 is effective against 5-fluorouracil resistance in colon cancer via suppressing EGFR and EGFR-mediated signaling pathways(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Xi, Changlei; Gong, Zhilin; Ye, Hui; Cao, Longlei; Yu, JieBackground. The identification of a sensitizing strategy to overcome 5-fluorouracil (5-FU) therapeutic resistance is needed in colon cancer. Recent studies highlight the oncogenic role of ubiquitin specific peptidase 8 (USP8) in many cancers. In line with these efforts, this work investigated the therapeutic potential of targeting USP8 in colon cancer. Methods. Immunohistochemistry was performed to determine USP8 expression level in colon cancer tissues and their adjacent normal tissues. Gain-of-function analysis via plasmid overexpression and loss-of-function analysis via siRNA knockdown were applied on cellular assays. The combinatory effects of USP8 inhibitor and cisplatin were determined using a colon xenograft mouse model. Immunoblotting was performed to investigate the molecular mechanism of USP8 inhibition in colon cancer cells. Results. Compared to normal counterparts, we showed that USP8 protein level was significantly higher in colon cancer tissues and cells. In addition, USP8 expression was not affected by prolonged exposure of colon cancer cells to 5-FU. USP8 was important for colon cancer cell growth and survival but not migration as assessed by loss-of-function and gain-of-function approaches. Pharmacological inhibition of USP8 using USP8 inhibitor is active against both sensitive and 5-FUresistant colon cancer cells. Of note, USP8 inhibitor significantly inhibited colon cancer formation and growth, and augmented in vivo efficacy of 5-FU without causing toxicity in mice. Mechanistic studies showed that USP8 inhibitor acted on colon cancer cells through suppressing EGFR and EGFR-mediated signalling pathways. Conclusions. Our work is the first to reveal the essential role of USP8 in colon cancer via EGFR oncogenic signalling pathways. Our findings provide a proof-of-concept that USP8 inhibitors are promising candidates to overcome 5-FU resistance in colon cancer
- PublicationRestrictedMicroRNAs expression in normal and malignant colon tissues as biomarkers of colorectal cancer and in response to pomegranate extracts consumption: critical issues to discern between modulatory effects and potential artefacts(Wiley, Wiley-VCH Verlag, 2015-07-20) Núñez Sánchez, María A.; Dávalos, Alberto; González-Sarrías, Antonio; Casas-Agustench, Patricia; Visioli, Francesco; Monedero Saiz, Tamara; García Talavera, Noelia V.; Gómez Sánchez, María B.; Sánchez-Álvarez, Carmen; García-Albert, Ana M.; Rodríguez-Gil, Francisco J.; Ruiz-Marín, Miguel; Pastor Quirante, Francisco A.; Martínez Díaz, Francisco; Tomás-Barberán, Francisco A.; García-Conesa, María Teresa; Espín, Juan Carlos; Oftalmología, Optometría, Otorrinolaringología y Anatomía PatológicaScope: MicroRNAs (miRs) are proposed as colorectal cancer (CRC) biomarkers. Pomegranate ellagic acid and their microbiota metabolites urolithins exert anticancer effects in preclinical CRC models, and target normal and malignant colon tissues in CRC patients. Herein, we investigated whether the intake of pomegranate extract (PE) modified miRs expression in surgical colon tissues versus biopsies from CRC patients. Methods and results: We conducted a randomized, double-blind, controlled trial. Thirty-five CRC patients consumed 900 mg PE daily before surgery. Control CRC patients (no PE intake, n = 10) were included. Our results revealed: (1) significant differences for specific miRs between malignant and normal tissues modifiable by the surgical protocols; (2) opposed trends between -5p and -3p isomolecules; (3) general induction of miRs attributable to the surgery; (4) moderate modulation of various miRs following the PE intake, and (5) no association between tissue urolithins and the observed miRs changes. Conclusion: PE consumption appears to affect specific colon tissue miRs but surgery critically alters miRs levels hindering the discrimination of significant changes caused by dietary factors and the establishment of genuine differences between malignant and normal tissues as biomarkers. The components responsible for the PE effects and the clinical relevance of these observations deserve further research.
- PublicationOpen AccessRole of fatty acids in malignancy and visual impairment, Epidemiological evidence and experimental studies(Murcia : F. Hernández, 2009) Tsubura, A.; Yuri, T.; Yoshizawa, K.; Uehara, N.; Takada, H.International variation in breast and colon cancer incidence is positively related to total fat intake. However, total fat consists of different fatty acid families, e.g., saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and n-3 and n-6 polyunsaturated fatty acids (PUFAs). Epidemiological evidence and experimental studies suggest that these fatty acid families have different effects on breast and colon carcinogenesis. Therefore the action of each fatty acid on carcinogenesis should be evaluated separately. Although it is difficult to establish firm conclusions on the effect of each fatty acid in human epidemiological studies, experimental studies on animals and cultured cells suggest that n-6 PUFAs (linoleic acid and arachidonic acid) may have a tumor promoting effect, while n-3 PUFAs (eicosapentaenoic acid, docosahexaenoic acid and a-linolenic acid) and conjugated fatty acids (CFAs; a mixture of positional and geometric isomers of PUFAs with conjugated double bonds) exert an inhibitory effect on tumor growth. SFAs such as palmitic acid and stearic acid show little or no tumor promoting effect, and the action of oleic acid, a MUFA, is inconclusive. In addition to regulation of abnormal cell growth seen in cancers, fatty acids also control cell loss seen in degenerative eye diseases, such as degeneration of lens material in cataract and degeneration of photoreceptor cells in retinitis pigmentosa. Experiments suggest that n-6 PUFAs cause deleterious effects, while n-3 PUFAs result in beneficial effects on the lens and retina. In particular, docosahexaenoic acid is known to be effective in rescuing photoreceptor cells from damage. Thus, understanding the function of each fatty acid is likely to be important for making progress in treating these and other diseases.
- PublicationOpen AccessSimultaneous phenotypic and genetic characterization of single circulating tumor cells from colon cancer patients(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Campos, María; Luque, Rafael; Jiménez, Juan; Martínez, Rafael; Warleta, Fernando; Sánchez-Quesada, Cristina; Delgado-Rodríguez, Miguel; Calvo, Alfonso; Gaforio, José J.Since circulating tumor cells (CTCs) have metastatic potential, their genetic and phenotypic characteristics could provide crucial information to establish the most effective therapy. We assessed the clinical utility of a methodology that allows the simultaneous analysis of CTC phenotype and genotype in colon cancer patients and, in addition, whether this methodology could provide complementary information to that obtained by the primary tumor biopsy. Thirty-three non-metastatic (stages 0-III) colon cancer patients and 9 healthy donor samples were evaluated. All peripheral blood samples (10 ml) were analyzed by cytokeratin immunomagnetic enrichment. Eight samples were analyzed by immunocytochemistry and 25 samples were analyzed by FICTION technique for simultaneous cytokeratin expression and chromosome 17 and ERBB2 gene status. A further study was carried out in one patient who showed CTC heterogeneity in chromosomal abnormalities. We analyzed HER2 protein expression on CTCs and FISH and HER2 protein expression in primary tumor of this patient. Our results show that 9.09% of patients had cytokeratin-positive CTCs (CK+/CTCs in peripheral blood). One of the patients showed heterogeneity in chromosomal 17 abnormalities and two different CK expression patterns on CTCs: one CK+/CTCs and one CK-/CTCs. Furthermore, 63.33% of these CTCs overexpressed HER2 protein while the primary tumor of this patient was diploid and did not express HER2 protein. We describe a methodology that allows the simultaneous genetic and phenotypic analysis of CTCs in colon cancer patients, which may provide essential information to select patients who might benefit from specific therapy.
- PublicationOpen AccessSurvivin and Cyclooxygenase-2 are co-expressed in human and mouse colon carcinoma and in terminally differentiated colonocytes(Murcia : F. Hernández, 2007) Mori, F.; Piro, F.R.; Della Rocca, C.; Mesiti, G.; Giampaoli, S.; Silvestre, G.; Lazzaro, D.In the evolution of colon rectal cancer (CRC) the imbalance between cell proliferation and apoptosis is considered one of the prominent causes of tumor induction and/or progression. In order to establish the role of anti apoptotic proteins in colon cancer development, we studied with immunohistochemical techniques the expression of Survivin in a mouse model of colon carcinogenesis induced by 1,2-dimethylhydrazine treatment. In this mouse model Survivin was over-expressed during tumor development, showing a distribution mimicking that described in the correspondent human malignancies. We also correlated Survivin distribution with COX-2 and ß-Catenin expression patterns. The co-localization of COX-2/ß-Catenin/Survivin in the same epithelial cells in tumor samples lends credence to possible in vivo regulatory effects of COX-2 and ß- Catenin on the intracellular Survivin levels in mouse and human colon cancer.
- PublicationRestrictedTargeted metabolic profiling of pomegranate polyphenols and urolithins in plasma, urine and colon tissues from colorectal cancer patients(Wiley, Wiley-VCH Verlag, 2014-02-16) Núñez Sánchez, María Angeles; García-Villalba, Rocío; Monedero Saiz, Tamara; García-Talavera, Noelia V.; Gómez Sánchez, María B.; Sánchez-Álvarez, Carmen; García-Albert, Ana M.; Rodríguez-Gil, Francisco J.; Ruiz-Marín, Miguel; Pastor Quirante, Francisco A.; Martínez Díaz, Francisco; Yáñez-Gascón, María J.; González-Sarrías, Antonio; Tomás-Barberán, Francisco A.; Espín, Juan C.; Oftalmología, Optometría, Otorrinolaringología y Anatomía PatológicaScope: Urolithins are bioactive metabolites produced by the gut microbiota from ellagitannins (ETs) and ellagic acid (EA). We investigated whether urolithins could be detected in colon tissues from colorectal cancer (CRC) patients after pomegranate extract (PE) intake. Methods and results: CRC patients (n = 52) were divided into controls and PEs consumers (900 mg/day for 15 days) before surgical resection. PEs with low (PE-1) and high (PE-2) punicalagin:EA ratio were administered. Twenty-three metabolites, but no ellagitannins, were detected in urine, plasma, normal (NT) or malignant (MT) colon tissues using UPLC-ESI-QTOF-MS/MS (UPLC, ultra performance liquid chromatography; QTOF, quadrupole TOF). Free EA, five EA conjugates, gallic acid and 12 urolithin derivatives were found in colon tissues. Individual and total metabolites levels were higher in NT than in MT, independently of the PE consumed. The maximal mean concentration (1671 ± 367 ng/g) was found in NT after consumption of PE-1 and the lowest concentration (42.4 ± 10.2 ng/g) in MT with PE-2. Urolithin A or isourolithin A were the main urolithins produced (54 and 46% patients with urolithin A or isourolithin A phenotype, respectively). High punicalagin content (PE-2) hampered urolithins formation. Conclusion: Significant levels of EA derivatives and urolithins are found in human colon tissues from CRC patients after consumption of pomegranate. Further studies are warranted to elucidate their biological activity.