Cellular localization of protein arginine methyltransferase-5 correlates with grade of lung tumors

Shilo, Konstantin; Wu, Xin; Sharma, Shivani; Welliver, M.X.; Duan, Wenrui; Villalona‐Calero, Miguel A.; Fukuoka, Junya; Sif, Saı̈d; Baiocchi, Robert A.; Hitchcock, Charles L.; Zhao, Weiqiang; Otterson, Gregory A.

doi:10.1186/1746-1596-8-201

Cited by 48 publications

(43 citation statements)

References 29 publications

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“…Among PRMTs, PRMT5 appears to play a particularly relevant role in the regulation of cell death and malignant transformation processes in mouse and humans (35–38). Indeed, PRMT5 is up-regulated in various human lymphoid malignancies (39–41) and solid tumors (42–48) and promotes cancer cell proliferation and survival (38, 46, 49, 50). This has led to the development of selective PRMT5-inhibiting drugs such as CMP5 and EPZ015666 as a potential new therapy in cancer (43, 51, 52).…”

Section: Introductionmentioning

confidence: 99%

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

Webb

Amici

Jablonski

et al. 2017

The Journal of Immunology

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In the autoimmune disease multiple sclerosis (MS) and its animal model Experimental Autoimmune Encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the Protein Arginine Methyl Transferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. Here, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently up-regulated during maximal proliferation of both mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in Delayed Type Hypersensitivity (DTH) and clinical disease in Experimental Autoimmune Encephalomyelitis (EAE) mouse models. These data implicate PRMT5 in regulation of adaptive memory T helper cell responses and suggest PRMT5 inhibitors may be a novel therapeutic approach for T cell-mediated inflammatory disease.

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Section: Introductionmentioning

confidence: 99%

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

Webb

Amici

Jablonski

et al. 2017

The Journal of Immunology

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“…The expression of PRMT5 has been studied in various types of cancers, and its localization, nuclear and/or cytoplasmic, appears to vary depending on the organs of origin and/or histological types . The diverse biological functions of PRMT5 may be explained by distinct intracellular localization and its binding partners.…”

Section: Discussionmentioning

confidence: 99%

Expression of protein arginine methyltransferase‐5 in oral squamous cell carcinoma and its significance in epithelial‐to‐mesenchymal transition

Amano

Matsubara

Yoshimoto

et al. 2018

Pathology International

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Protein arginine methyltransferases (PRMT) 5, a member of type II arginine methyltransferases, catalyzes the symmetrical dimethylation of arginine residues on histone and non-histone substrates. Although the overexpression of PRMT5 has been reported in various cancers, its role in oral squamous cell carcinoma (OSCC) has not been elucidated. In the present study, we immunohistochemically examined the expression of PRMT5 in surgically resected oral epithelial dysplasia (OED, n = 8), oral intraepithelial neoplasia (OIN)/carcinoma in situ (CIS) (n = 11) and OSCC (n = 52) with or without contiguous OED lesions. In the normal epithelium, PRMT5 was weakly expressed in the cytoplasm of basal layer cells. In OED, OIN/CIS, and OSCC, its expression consistently and uniformly increased in the cytoplasm of dysplastic and cancer cells. Moreover, nuclear and cytoplasmic localization was detected in the invasive front of cancer cells, particularly in cases showing poor differentiation or aggressive invasion patterns. The concomitant nuclear and cytoplasmic expression of PRMT5 correlated with the loss of E-cadherin and cytokeratin 17, and the upregulation of vimentin, features that are both indicative of epithelial-to-mesenchymal transition. PRMT5 may play a role from early oncogenesis through to the progression of OSCC, particularly in the aggressive mode of stromal invasion.

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“…Furthermore, many previous studies showed the expression and functions of proteins and genes in lung cancer, and it may be significantly related to tumor progression and metastasis [23-26]. …”

Section: Discussionmentioning

confidence: 99%

Histological comparison between preoperative and surgical specimens of non-small cell lung cancer for distinguishing between "squamous" and "non-squamous" cell carcinoma

et al. 2014

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BackgroundNon-small cell lung cancers (NSCLCs) are frequently heterogeneous and in approximately 70% of cases, NSCLCs are diagnosed and staged by small biopsies or cytology rather than by examination of surgically resected specimens. Thus, in most patients, the diagnosis is established based on examination of preoperative specimens alone. Recently, classification of NSCLC into pathologic subtypes has been shown to be important for selecting the appropriate systemic therapy, from both the point of view of treatment efficacy and prevention of toxicity.MethodsWe retrospectively reviewed the data of 225 patients to compare the preoperative classification of the NSCLC subtype on biopsy specimens with the postoperative classification based on examination of the resected specimens, in order to compare the accuracy of the two for the diagnosis of various histological subtypes of NSCLC.ResultsIn 169 of the 225 (75.1%) patients, the preoperative diagnosis was definite malignancy. Histologically, the final pathologic diagnosis made from the surgical specimens was adenocarcinoma (ADC) in 169 patients, and in 75.5% of these cases, the diagnosis was concordant with the preoperative diagnosis. Among the patients who had squamous cell carcinoma (SQC) in the preoperative specimens, the diagnosis was concordant with the preoperative diagnosis in 65.7% of cases. Misclassified preoperative biopsies included an even number of SQCs and ADCs, with all the misclassified biopsies being ADCs morphologically mimicking SQC due to solid growth. Significantly higher specificity, negative predictive value and accuracy were observed for the diagnosis of SQC.ConclusionsOur study suggested that the concordance rates for diagnosis of the NSCLC subtypes, especially the "squamous" or "non-squamous" histologies, between preoperative and surgical specimens were satisfactory, as compared with previous reports. Therefore, pretreatment diagnosis of lung cancer using small samples is reasonable for selecting the optimal treatment. However, in order not to lose the opportunity for selecting an effective treatment, we should be aware that the diagnosis in preoperative small samples might be different from that based on examination of the surgical specimens.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2032698427120488

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Cellular localization of protein arginine methyltransferase-5 correlates with grade of lung tumors

Cited by 48 publications

References 29 publications

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

Expression of protein arginine methyltransferase‐5 in oral squamous cell carcinoma and its significance in epithelial‐to‐mesenchymal transition

Histological comparison between preoperative and surgical specimens of non-small cell lung cancer for distinguishing between "squamous" and "non-squamous" cell carcinoma

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