Association of epithelial-mesenchymal transition and nuclear cofilin with advanced urothelial cancer

Hensley, Patrick J.; Zetter, Daniel; Horbinski, Craig; Kyprianou, Natasha

doi:10.1016/j.humpath.2016.06.020

Cited by 25 publications

(22 citation statements)

References 33 publications

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“…In addition, cofilin-1 is part of the RNA polymerase II transcriptional machinery with a role in transcriptional elongation [ 35 ]. Consistent with our results, recent evidence showed an association between the nuclear localization of cofilin-1 and bladder cancer progression [ 36 ]. Furthermore, a partial nuclear translocation of phosphorylated/inactive cofilin-1 was observed in colon adenocarcinoma cell lines characterized by an invasive phenotype [ 37 ].…”

Section: Discussionsupporting

confidence: 93%

Cofilin-1 levels and intracellular localization are associated with melanoma prognosis in a cohort of patients

et al. 2018

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Melanoma is an aggressive cancer with highly metastatic ability. We propose cofilin-1, a key protein in the regulation of actin dynamics and migration, as a prognostic marker. We determined cofilin-1 levels in a retrospective cohort of patients with melanomas and benign lesions of melanocytes (nevi) by immunohistochemistry. Higher cofilin-1 levels were found in malignant melanoma (MM) with Breslow Index (BI)>2 vs MM with BI<2, melanoma in situ (MIS) and nevi and also in MM with metastasis vs MM without detected metastasis. Kaplan-Meier survival curves were performed, clustering patients according to either the type of melanocytic lesions or cofilin-1 level. Survival curves demonstrated worse prognosis of patients with high vs low cofilin-1 levels. TCGA database analysis of melanoma also showed low survival in patients with upregulated cofilin-1 mRNA vs patients without alteration in CFL1 mRNA expression. As cofilin-1 has a dual function depending on its intracellular localization, we evaluated nuclear and cytoplasmic levels of cofilin-1 in melanoma and nevi samples by immunofluorescence. MM with high Breslow index and metastatic cells not only presented cytoplasmic cofilin-1, but also showed this protein at the nucleus. An increase in nuclear/cytoplasmic cofilin-1 mean fluorescence ratio was observed in MM with BI>2 vs MM with BI<2, MIS and nevi.In conclusion, an association of cofilin-1 levels with malignant features and an inverse correlation with survival were demonstrated. Moreover, this study suggests that not only the higher levels of cofilin-1, but also its nuclear localization can be proposed as marker of worse outcome of patients with melanoma.

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Section: Discussionsupporting

confidence: 93%

Cofilin-1 levels and intracellular localization are associated with melanoma prognosis in a cohort of patients

et al. 2018

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“…Cofilin overexpression has been seen in lung cancer cells undergoing EMT [ 48 ] and in association with increased tumor cell invasion or metastasis [ 34 , 49 – 51 ]. Collazo and coworkers reported augmented levels of active cofilin in human prostate cancer and in experimental prostate tumors [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Alendronate-induced disruption of actin cytoskeleton and inhibition of migration/invasion are associated with cofilin downregulation in PC-3 prostate cancer cells

et al. 2018

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Bisphosphonates are used for prevention of osteoporosis and metastatic bone diseases. Anti-invasive effects on various cancer cells have also been reported, but the mechanisms involved are not well-understood. We investigated the effects of the nitrogen-containing bisphosphonate alendronate (ALN) on the regulation of actin cytoskeleton in PC-3 cells. We analyzed the ALN effect on the organization and the dynamics of actin, and on the cytoskeleton-related regulatory proteins cofilin, p21-associated kinase 2 (PAK2), paxillin and focal adhesion kinase. Immunostainings of cofilin in ALN-treated PC-3 cells and xenografts were performed, and the role of cofilin in ALN-regulated F-actin organization and migration/invasion in PC-3 cells was analyzed using cofilin knockdown and transfection. We demonstrate that disrupted F-actin organization and decreased cell motility in ALN-treated PC-3 cells were associated with decreased levels of total and phosphorylated cofilin. PAK2 levels were also lowered but adhesion-related proteins were not altered. The knockdown of cofilin similarly impaired F-actin organization and decreased invasion of PC-3 cells, whereas in the cells transfected with a cofilin expressing vector, ALN treatment did not decrease cellular cofilin levels and migration as in mock transfected cells. ALN also reduced immunohistochemical staining of cofilin in PC-3 xenografts. Our results suggest that reduction of cofilin has an important role in ALN-induced disruption of the actin cytoskeleton and inhibition of the PC-3 cell motility and invasion. These data also support the idea that the nitrogen-containing bisphosphonates could be efficacious in inhibition of prostate cancer invasion and metastasis, if delivered in a pharmacological formulation accessible to the tumors.

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“…It may play a role in tumor development and be an important early-diagnosis biomarker of tumors [ 28 – 33 ]. Ensley and others proposed that cofilin is significantly upregulated in several tumors and is associated with malignant progression; indeed, cofilin is considered a potential tumor biomarker and a molecular target for the treatment of bladder cancer [ 34 , 35 ]. In addition, high expression of cofilin in tumor cells is associated with shorter overall survival, indicating that it is a prognostic factor for tumors and can be used as a potential therapeutic target [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Cofilin-2 Acts as a Marker for Predicting Radiotherapy Response and Is a Potential Therapeutic Target in Nasopharyngeal Carcinoma

Lin

et al. 2018

Med Sci Monit

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BackgroundThe purpose of this study was to determine whether cofilin-2 could serve as a protein marker for predicting radiotherapy response and as a potential therapeutic target in nasopharyngeal carcinoma (NPC).Material/MethodsCofilin-2 protein levels in serum and tissue samples from patients with NPC were assessed by sandwich ELISA and IHC. In vitro, cofilin-2 levels in CNE-2R cells were significantly higher than those of CNE-2 cells. Meanwhile, CNE-2R cells were silenced for cofilin-2 to obtain a stable cofilin-2-RNAi-LV3 cell line. Then, cell proliferation, radiosensitivity, invasion and migration abilities, cell cycle, and apoptosis were evaluated by Cell Counting Kit 8 assay (CCK-8), flow cytometry (FCM), clone formation assay, and in vitro.ResultsThe secreted levels of the cofilin-2 protein in radioresistant NPC patients were significantly higher than those of radiosensitive cases. After cofilin-2 knockdown in nasopharyngeal carcinoma CNE-2R cells, proliferation was decreased, while apoptosis and radiosensitivity were enhanced; cell cycle distribution was altered, and the transplanted tumors in nude mice grew significantly less.ConclusionsOverall, our findings suggest that cofilin-2 acts as a marker for predicting radiotherapy response and is a potential therapeutic target in nasopharyngeal carcinoma.

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Association of epithelial-mesenchymal transition and nuclear cofilin with advanced urothelial cancer

Cited by 25 publications

References 33 publications

Cofilin-1 levels and intracellular localization are associated with melanoma prognosis in a cohort of patients

Cofilin-1 levels and intracellular localization are associated with melanoma prognosis in a cohort of patients

Alendronate-induced disruption of actin cytoskeleton and inhibition of migration/invasion are associated with cofilin downregulation in PC-3 prostate cancer cells

Cofilin-2 Acts as a Marker for Predicting Radiotherapy Response and Is a Potential Therapeutic Target in Nasopharyngeal Carcinoma

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