Loss of neural crest‐associated gene <i>FOXD1</i> impairs melanoma invasion and migration <i>via RAC1B</i> downregulation

Wu, Huizi; Larribère, Lionel; Sun, Qian; Novak, Daniel; Sachindra, Sachindra; Granados, Karol; Umansky, Viktor; Utikal, Jochen

doi:10.1002/ijc.31799

Cited by 28 publications

(38 citation statements)

References 29 publications

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“…Deep understanding of cancer regulatory networks has a potential of providing a guidance for developing new anti‐tumor treatment strategies. OSCC initiation and progression have multiple consecutive histopathological stages, which are driven by oncogene activation and tumor suppressor dysfunction 21 . Transcription factor (TF) disorders have been reported to be closely related to the development of tumors, and targeting TFs may be an effective strategy for cancer intervention 5 .…”

Section: Discussionmentioning

confidence: 99%

Increased expression of FOXD1 is associated with cervical node metastasis and unfavorable prognosis in oral squamous cell carcinoma

Yan

et al. 2020

J Oral Pathology Medicine

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Background Previous studies suggest that FOXD1 is involved in tumorigenesis and closely related to the patients’ poor outcome in human cancer. However, its expression pattern in primary oral squamous cell carcinoma (OSCC) remains uncovered. In this study, we tried to explore the expression pattern of FOXD1 and its clinicopathological significance in primary OSCC. Methods Data mining and analysis on FOXD1 mRNA expression in OSCC samples were performed using publicly available databases. Its protein expression was supervised by immunohistochemistry in a retrospective cohort containing 58 primary OSCC samples. Furthermore, the potential associations between FOXD1 expression and various clinicopathological characteristics and patients’ survival were further investigated. Results Bioinformatic analysis indicated that FOXD1 mRNA abundance was obviously up‐regulated in OSCC cohorts. Immunohistochemical staining results showed that FOXD1 protein was significantly up‐regulated in OSCC specimens as compared to normal counterparts and its aberrant up‐regulation was remarkably related to cervical lymph node metastasis (P = .0198) and decreased overall survival (P = .0281) and disease‐free survival (P = .0312). Both univariate and multivariate Cox regression analysis further revealed the expression pattern of FOXD1 as an independent prognostic factor for overall survival of patients. Conclusion Taken together, these findings indicate that the aberrant up‐regulation of FOXD1 is related to cervical node metastasis and unfavorable prognosis in OSCC and it also may play a key role during OSCC tumorigenesis and regard as a novel diagnostic and prognostic biomarker for OSCC.

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Section: Discussionmentioning

confidence: 99%

Increased expression of FOXD1 is associated with cervical node metastasis and unfavorable prognosis in oral squamous cell carcinoma

Yan

et al. 2020

J Oral Pathology Medicine

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“…Moreover, FOXD1 overexpression increases the invasion rate of melanoma cell lines, and the additional silencing of the tumor-associated gene RAC1B can suppress this increase. These data suggest that FOXD1 is a strong candidate for an important role in therapy resistance of melanoma [ 17 ]. Indeed, FOXD1 can promote drug resistance of breast cancer [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we generated human melanoblasts either by dedifferentiation of mature melanocytes or differentiation of pluripotent stem cells [ 15 , 16 , 17 , 18 ]. We describe how transcriptomic data from human melanoblasts could help to better understand drug resistance features of melanoma cells.…”

Section: Introductionmentioning

confidence: 99%

Targeted Therapy-Resistant Melanoma Cells Acquire Transcriptomic Similarities with Human Melanoblasts

Larribère

Kuphal

Sachpekidis

et al. 2018

Cancers

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The mechanisms of adaptive and acquired drug resistance in tumors are not completely understood. So far, gene amplifications or mutations, leading to the reactivation of the MAPK or PI3K pathways have been described. In this study, we used two different methods to generate human melanoblasts: (1) via differentiation from induced pluripotent stem cells (iPSCs) and (2) via dedifferentiation from melanocytes. The melanoblast transcriptomes were then compared to the transcriptome of MAPK inhibitor-resistant melanoma cells. We observed that the expression of genes associated with cell cycle control, DNA damage control, metabolism, and cancer was altered in both melanoblast populations and in both adaptive and acquired resistant melanoma samples, compared to drug-sensitive samples. However, genes involved in antigen presentation and cellular movement were only regulated in the melanoblast populations and in the acquired resistant melanoma samples, compared to the drug-sensitive samples. Moreover, melanocyte-derived melanoblasts and adaptive resistant melanoma samples were characterized by different expression levels of certain transcription factors or genes involved in the CDK5 pathway. In conclusion, we show here that in vitro models of human melanoblasts are very important tools to comprehend the expression profiles of drug-resistant melanoma.

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“…In glioma, FOXD1 upregulates ALDH1A3 to promote stemness properties [13]. FOXD1 also targets RAC1B to regulate melanoma cell motility [17]. However, the downstream target involved in FOXD1 in lung cancer remains to be characterized.…”

Section: Discussionmentioning

confidence: 99%

“…FOXD1 overexpression is strongly associated with NSCLC proliferation and metastasis through the activation of vimentin [16]. Although several studies have tried to unravel the molecular networks of FOXD1 [11][12][13]16,17], the molecular mechanisms related to FOXD1 remain largely unexamined, especially in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

FOXD1 and Gal-3 Form a Positive Regulatory Loop to Regulate Lung Cancer Aggressiveness

Chang

Hsiao

et al. 2019

Cancers

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Dysregulation of forkhead box D1 (FOXD1) is known to promote tumor progression; however, its molecular mechanism of action is unclear. Based on microarray analysis, we identified galectin-3/LGALS3 (Gal-3) as a potential downstream target of FOXD1, as FOXD1 transactivated Gal-3 by interacting with the Gal-3 promoter to upregulate Gal-3 in FOXD1-overexpressing CL1-0 lung cancer cells. Ectopic expression of FOXD1 increased the expression of Gal-3 and the growth and motility of lung cancer cells, whereas depletion of Gal-3 attenuated FOXD1-mediated tumorigenesis. ERK1/2 interacted with FOXD1 in the cytosol and translocated FOXD1 into the nucleus to activate Gal-3. Gal-3 in turn upregulated FOXD1 via the transcription factor proto-oncogene 1 (ETS-1) to transactivate FOXD1. The increase in ETS-1/FOXD1 expression by Gal-3 was through Gal-3-mediated integrin-β1 (ITGβ1) signaling. The overexpression of both FOXD1 and Gal-3 form a positive regulatory loop to promote lung cancer aggressiveness. Moreover, both FOXD1 and Gal-3 were positively correlated in human lung cancer tissues. Our findings demonstrated that FOXD1 and Gal-3 form a positive feedback loop in lung cancer, and interference of this loop may serve as an effective therapeutic target for the treatment of lung cancers, particularly those related to dysregulation of Gal-3.

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Loss of neural crest‐associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation

Cited by 28 publications

References 29 publications

Increased expression of FOXD1 is associated with cervical node metastasis and unfavorable prognosis in oral squamous cell carcinoma

Increased expression of FOXD1 is associated with cervical node metastasis and unfavorable prognosis in oral squamous cell carcinoma

Targeted Therapy-Resistant Melanoma Cells Acquire Transcriptomic Similarities with Human Melanoblasts

FOXD1 and Gal-3 Form a Positive Regulatory Loop to Regulate Lung Cancer Aggressiveness

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