Possible Role of the <i>RORC</i> Gene in Primary and Secondary Lymphedema: Review of the Literature and Genetic Study of Two Rare Causative Variants

Michelini, Sandro; Ricci, Maurizio; Serrani, Roberta; Stuppia, Liborio; Beccari, Tommaso; Vešelényiová, Dominika; Kenanoğlu, Sercan; Barati, Shila; Kurti, Danjela; Baglivo, Mirko; Basha, Syed Hussain; Krajčovič, Juraj; Dündar, Munis; Bertelli, Matteo

doi:10.1089/lrb.2020.0030

Cited by 5 publications

(4 citation statements)

References 27 publications

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“…miR-20b was identified to target RORC and decrease Th17 cell differentiation in experimental autoimmune encephalomyelitis (Pan et al, 2015). Although the results of this study were reported in an autoimmune disease model, the Rorγ protein is encoded by RORC, a gene that was highly correlated with lymph node organogenesis (Massoud et al, 2016), filariasis, (Rajasekaram et al, 2017) and secondary lymphedema (Newman et al, 2012;Michelini et al, 2020). A LEC marker, forkhead box O1 (Foxo1), was demonstrated to interact with Rorγ, resulting in the regulation of Th17 cell pathogenicity and IL-17A production.…”

Section: Mirnas and Immune-lymphatic Dysregulationmentioning

confidence: 81%

Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema

Yusof

Groen

Rosli

et al. 2021

Front. Cell Dev. Biol.

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Secondary lymphedema is characterized by lymphatic fluid retention and subsequent tissue swelling in one or both limbs that can lead to decreased quality of life. It often arises after loss, obstruction, or blockage of lymphatic vessels due to multifactorial modalities, such as lymphatic insults after surgery, immune system dysfunction, deposition of fat that compresses the lymphatic capillaries, fibrosis, and inflammation. Although secondary lymphedema is often associated with breast cancer, the condition can occur in patients with any type of cancer that requires lymphadenectomy such as gynecological, genitourinary, or head and neck cancers. MicroRNAs demonstrate pivotal roles in regulating gene expression in biological processes such as lymphangiogenesis, angiogenesis, modulation of the immune system, and oxidative stress. MicroRNA profiling has led to the discovery of the molecular mechanisms involved in the pathophysiology of auto-immune, inflammation-related, and metabolic diseases. Although the role of microRNAs in regulating secondary lymphedema is yet to be elucidated, the crosstalk between microRNAs and molecular factors involved in the pathological features of lymphedema, such as skin fibrosis, inflammation, immune dysregulation, and aberrant lipid metabolism have been demonstrated in several studies. MicroRNAs have the potential to serve as biomarkers for diseases and elucidation of their roles in lymphedema can provide a better understanding or new insights of the mechanisms underlying this debilitating condition.

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Section: Mirnas and Immune-lymphatic Dysregulationmentioning

confidence: 81%

Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema

Yusof

Groen

Rosli

et al. 2021

Front. Cell Dev. Biol.

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“…Other candidate genes are correlated with SOX18 expression: VCAM1 expression is increased by SOX18, while GDF2 signaling reduces SOX18 expression [81,82]. RORC and SMARCA4 influence LECs' fate determination [83], while HOX10 is proven to reduce RhoC expression, influencing cytoskeletal organization [84]. Finally, ERK and AKT activity can stimulate different transcription factors, among which are PROX1 and NFATC1 (stimulated by ERK) and FOXC1 (stimulated by both AKT and EKR) [38,85].…”

Section: Transcription Factorsmentioning

confidence: 99%

Low Efficacy of Genetic Tests for the Diagnosis of Primary Lymphedema Prompts Novel Insights into the Underlying Molecular Pathways

Bonetti

Paolacci

Samaja³

et al. 2022

IJMS

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Lymphedema is a chronic inflammatory disorder caused by ineffective fluid uptake by the lymphatic system, with effects mainly on the lower limbs. Lymphedema is either primary, when caused by genetic mutations, or secondary, when it follows injury, infection, or surgery. In this study, we aim to assess to what extent the current genetic tests detect genetic variants of lymphedema, and to identify the major molecular pathways that underlie this rather unknown disease. We recruited 147 individuals with a clinical diagnosis of primary lymphedema and used established genetic tests on their blood or saliva specimens. Only 11 of these were positive, while other probands were either negative (63) or inconclusive (73). The low efficacy of such tests calls for greater insight into the underlying mechanisms to increase accuracy. For this purpose, we built a molecular pathways diagram based on a literature analysis (OMIM, Kegg, PubMed, Scopus) of candidate and diagnostic genes. The PI3K/AKT and the RAS/MAPK pathways emerged as primary candidates responsible for lymphedema diagnosis, while the Rho/ROCK pathway appeared less critical. The results of this study suggest the most important pathways involved in the pathogenesis of lymphedema, and outline the most promising diagnostic and candidate genes to diagnose this disease.

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“…RORγ T, a RORC-encoded protein, is the key transcription factor responsible for Th17 polarization and function, as well as thymocyte development ( Yahia-Cherbal et al, 2019 ). Studies have shown that RORC plays an important role in autoimmunity and inflammation ( IvanovMcKenzie et al, 2006 ; Michelini et al, 2021 ). Several studies have shown that RORC performs critical regulatory functions in cell proliferation, metastasis, and chemoresistance in various malignancies such as hematologic tumors ( Subramanian et al, 2019 ), breast cancer ( Oh et al, 2014 ), bladder cancer ( Cao et al, 2019 ), and melanoma ( Brożyna et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

A comprehensive pancancer analysis reveals the potential value of RAR-related orphan receptor C (RORC) for cancer immunotherapy

Sun

et al. 2022

Front. Genet.

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Background: RAR-related orphan receptor C (RORC) plays an important role in autoimmune responses and inflammation. However, its function in cancer immunity is still unclear. Its potential value in cancer immunotherapy (CIT) needs to be further studied.Methods: Expression and clinical data for 33 cancers were obtained from UCSC-Xena. The correlation between RORC expression and clinical parameters was analyzed using the limma software package to assess the prognostic value of RORC. Timer2.0 and DriverDBv3 were used to analyze the RORC mutation and methylation profiles. RORC-associated signaling pathways were identified by GSEA. The correlations of RORC expression with tumor microenvironment factors were further assessed, including immune cell infiltration (obtained by CIBERSORT) and immunomodulators (in pancancer datasets from the Tumor-Immune System Interactions and Drug Bank [TISIDB] database). In addition, the correlations of RORC with four CIT biomarkers (tumor mutational burden, microsatellite instability, programmed death ligand-1, and mismatch repair) were explored. Furthermore, three CIT cohorts (GSE67501, GSE168204, and IMvigor210) from the Gene Expression Omnibus database and a previously published study were used to determine the association between RORC expression and CIT response.Results: RORC was differentially expressed in many tumor tissues relative to normal tissues (20/33). In a small number of cancers, RORC expression was correlated with age (7/33), sex (4/33), and tumor stage (9/33). Furthermore, RORC expression showed prognostic value in many cancers, especially in kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and mesothelioma (MESO). The mutation rate of RORC in most cancer types was low, while RORC was hypermethylated or hypomethylated in multiple cancers. RORC was associated with a variety of biological processes and signal transduction pathways in various cancers. Furthermore, RORC was strongly correlated with immune cell infiltration, immunomodulators, and CIT

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Possible Role of the RORC Gene in Primary and Secondary Lymphedema: Review of the Literature and Genetic Study of Two Rare Causative Variants

Cited by 5 publications

References 27 publications

Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema

Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema

Low Efficacy of Genetic Tests for the Diagnosis of Primary Lymphedema Prompts Novel Insights into the Underlying Molecular Pathways

A comprehensive pancancer analysis reveals the potential value of RAR-related orphan receptor C (RORC) for cancer immunotherapy

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