Tumor suppressor activity and inactivation of galanin receptor type 2 by aberrant promoter methylation in head and neck cancer

Misawa, Yuki; Misawa, Kiyoshi; Kanazawa, Takemichi; Uehara, Takayuki; Endo, Shori; Mochizuki, Daiki; Yamatodani, Takashi; Carey, Thomas E.; Mineta, Hiroyuki

doi:10.1002/cncr.28411

Cited by 32 publications

(41 citation statements)

References 25 publications

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“…[16] Furthermore, the methylation of galanin significantly correlated with GALR1 and GALR2 methylation and reduced DFS. [4,5,15] The methylation of the gene pair of galanin and GALR1 in the primary tumor was associated with the most significant odds ratio of recurrence, [15] while another study concluded that GALR1 induces cell cycle arrest, and GALR2 induces both cell cycle arrest and apoptosis in HNSCC following galanin treatment. [24] this study shows that aberrant DNA methylation of SST and SSTR1 is not associated with prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…[18] UM-SCC cell lines were kindly provided by Dr. Thomas E. Carey of the University of Michigan and were validated by genotyping in his laboratory. [4,5]…”

Section: Methodsmentioning

confidence: 99%

“…Q-MSP was carried out and the normalized methylation value (NMV) was defined as described previously. [4] To analyze the methylation status of TAC1 [16], TACR1 [16], Galanin [15], GALR1 [4] and GALR2 [5] primers, conditions, as described previously, were used.…”

Section: Methodsmentioning

confidence: 99%

“…[3] Our findings suggest that simultaneous methylation of galanin , galanin receptor type 1 ( GALR1 ), and GALR2 genes occurs in a subset of HNSCC and may be used as a prognostic marker. [4,5] Somatostatin (SST) was first identified as a growth hormone release-inhibitory factor in ovine hypothalamus in 1973. [6] Its main functions involve regulating endocrine and exocrine secretion, modulating motor activity, and inhibiting gastrin-stimulated gastric acid secretion in the gastrointestinal tract.…”

Section: Introductionmentioning

confidence: 99%

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Aberrant Methylation Inactivates Somatostatin and Somatostatin Receptor Type 1 in Head and Neck Squamous Cell Carcinoma

Misawa

Kondo

et al. 2015

PLoS ONE

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PurposeThe aim of this study was to define somatostatin (SST) and somatostatin receptor type 1 (SSTR1) methylation profiles for head and neck squamous cell carcinoma (HNSCC) tumors at diagnosis and follow up and to evaluate their prognostic significance and value as a biomarker.MethodsGene expression was measured by quantitative RT-PCR. Promoter methylation status was determined by quantitative methylation-specific PCR (Q-MSP) in HNSCC.ResultsMethylation was associated with transcription inhibition. SST methylation in 81% of HNSCC tumor specimens significantly correlated with tumor size (P = 0.043), stage (P = 0.008), galanin receptor type 2 (GALR2) methylation (P = 0.041), and tachykinin-1 (TAC1) (P = 0.040). SSTR1 hypermethylation in 64% of cases was correlated with tumor size (P = 0.037), stage (P = 0.037), SST methylation (P < 0.001), and expression of galanin (P = 0.03), GALR2 (P = 0.014), TAC1 (P = 0.023), and tachykinin receptor type 1 (TACR1) (P = 0.003). SST and SSTR1 promoter hypermethylation showed highly discriminating receiver operator characteristic curve profiles, which clearly distinguished HNSCC from adjacent normal mucosal tissues. Concurrent hypermethylation of galanin and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.0001). Among patients with oral cavity and oropharynx cancer, methylation of both SST and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.028). In multivariate logistic-regression analysis, concomitant methylation of galanin and SSTR1 was associated with an odds ratio for recurrence of 12.53 (95% CI, 2.62 to 59.8; P = 0.002).ConclusionsCpG hypermethylation is a likely mechanism of SST and SSTR1 gene inactivation, supporting the hypothesis that SST and SSTR1 play a role in the tumorigenesis of HNSCC and that this hypermethylation may serve as an important biomarker.

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Section: Discussionmentioning

confidence: 99%

“…[18] UM-SCC cell lines were kindly provided by Dr. Thomas E. Carey of the University of Michigan and were validated by genotyping in his laboratory. [4,5]…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Aberrant Methylation Inactivates Somatostatin and Somatostatin Receptor Type 1 in Head and Neck Squamous Cell Carcinoma

Misawa

Kondo

et al. 2015

PLoS ONE

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“…Орексин-А стимулирует аутофагию опухолевых клеток (линия HCT-116, карцинома прямой кишки) за счет мо-дуляции сигнального пути ERK, поддерживающего ба-ланс между выживанием и апоптозом клеток [16]. Низкая активность рецепторов галанина (например при избыточ-ном метилировании участков ДНК, кодирующих гены этих рецепторов) стимулирует рост опухолей головы и шеи [17,18].…”

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Evaluation of the antitumor potential of cerebrolysin

Gromova

Пронин

Torshin

et al. 2016

Z. nevrol. psikhiatr. im. S.S. Korsakova

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Препарат церебролизин, основой которого является высокоочищенный экстракт пептидов головного мозга молодых свиней, успешно используется в клинической практике для восстановления неврологических функций пациентов с инсультом, деменцией и черепно-мозговой травмой. Известно, что применение церебролизина до-стоверно уменьшает неврологический дефицит [1], сни-жает объем зоны инфаркта при инсульте [2], оказывает нейрорегенеративное [3], противоспалительное и антиок-сидантное действие [4,5]. Также на модели у животных (крысы линии Вистар) тиосемикарбазидовых судорог бы-ло показано, что церебролизин обладает противосудорож-ными эффектами [6]. Цель исследования. изучение влияния церебролизина на рост и метастазирование злокачественных новообразований у мышей (модель карциномы легких льюис). Материал и методы. исследование проведено на 60 самцах мышей-гибридов F 1 (возраст 2-2,5 мес, масса тела 19-22 г). В качестве опухолевой модели использована перевиваемая эпидермоидная карцинома легких льюис (Клл) -стандартная экспериментальная модель для оценки свойств потенциальных противоопухолевых средств. Животным со 2 по 16-е сутки после трансплантации опухоли ежедневно вводили церебролизин путем однократной внутрибрюшинной инъекции в дозах 524 мг/кг (n=20) и 1800 мг/кг (n=20). Результаты и заключение. По сравнению с контрольной группой (n=20) отмечено торможение роста Клл в период проведения терапии (с 7 по 16-е сутки). Воздействие препарата сопровождалось торможением скорости роста опухоли на 10-15% (р<0,05). Установлен дозозависимый эффект снижения числа крупных метастазов: с повышением дозы церебролизина число крупных метастазов статистически значимо снижалось на 30-50% (р=0,01). Сделан вывод, что церебролизин достоверно подавляет интенсивность роста карциномы легких льюис. Objective. To investigate the effect of cerebrolysin on the growth and metastasis of malignant tumors in mice (a model of lung carcinoma lewis). Material and methods. The study was performed on 60 male mice, hybrids F1 (the age of 2-2.5 months, body weight 19-22g.). Transplantable epidermoid lewis lung carcinoma (llC) was used as a standard experimental model to evaluate the properties of the potential antitumor agents. experimental animals were administered a single intraperitoneal injection of cerebrolysin in doses of 524 mg/kg (n=20) and 1800 mg/kg (n=20) daily from 2 to 16 days after tumor transplantation. Results and conclusion. Compared with the control group (n=20), cerebrolysin induced growth inhibition of llC during the treatment (7 to 16 days). An impact of the drug was accompanied by the inhibition of the tumor growth rate by 10-15% (p<0.05). Cerebrolysin demonstrated a dose-dependent effect of reducing the large number of metastases: a number of large metastases significantly decreased by 30-50% with the increase of cerebrolysin dose (p=0.01). Cerebrolysin can significantly suppress the growth rate of lewis lung carcinoma.

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The GAL/GALR2 axis promotes the perineural invasion of salivary adenoid cystic carcinoma via epithelial‐to‐mesenchymal transition

et al. 2022

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Background: Perineural invasion (PNI) is a typical pathological characteristic of salivary adenoid cystic carcinoma (SACC) and other neurotrophic cancers. The mechanism of the neural microenvironment controlling tumor progression during the PNI process is unclear. In the present study, we investigated the role and molecular mechanisms of nerve-derived neuropeptide galanin (GAL) and its receptor (GALR2) in the regulation of PNI in SACC. Methods: Immunohistochemistry staining and clinical association studies were performed to analyze the expression of GAL and GALR2 in SACC tissues and their clinical value. Dorsal root ganglion or SH-SY5Y cells were co-cultured with SACC cells in vitro to simulate the interactions between the neural microenvironment and tumor cells, and a series of assays including transcriptome sequencing, Western blot, and Transwell were performed to investigate the role and molecular mechanism of GAL and GALR2 in the regulation of SACC cells. Moreover, both the in vitro and in vivo PNI models were established to assess the potential PNI-specific therapeutic effects by blocking the GAL/GALR2 axis. Results: GAL and GALR2 were highly expressed in SACC tissues, and were associated with PNI and poor prognosis in SACC patients (p < 0.05). Nerve-derived GAL activated GALR2 expression in SACC cells and induced epithelial-tomesenchymal transition (EMT) in SACC cells. Adding human recombinant GAL to the co-culture system promoted the proliferation, migration, and invasion of SACC cells significantly, but inhibited the apoptosis of SACC cells. Adding M871, a specific antagonist of GALR2, significantly blocked the above effects (p < 0.05) and inhibited the PNI of SACC cells in vitro and in vivo (p < 0.05). Conclusions: This study demonstrated that nerve-derived GAL activated GALR2 expression, and promoted EMT in SACC cells, thereby enhancing the | 4497 WANG et al. How to cite this article: Wang J, Yang Z, Liu Y, et al. The GAL/GALR2 axis promotes the perineural invasion of salivary adenoid cystic carcinoma via epithelial-to-mesenchymal transition.

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Tumor suppressor activity and inactivation of galanin receptor type 2 by aberrant promoter methylation in head and neck cancer

Abstract: Frequent promoter hypermethylation in association with prognosis, and growth suppression after re-expression, supports the hypothesis that GALR2 may act to suppress tumor activity. GALR2 is a potentially significant therapeutic target and prognostic factor for this cancer type.

Cited by 32 publications

References 25 publications

Aberrant Methylation Inactivates Somatostatin and Somatostatin Receptor Type 1 in Head and Neck Squamous Cell Carcinoma

Aberrant Methylation Inactivates Somatostatin and Somatostatin Receptor Type 1 in Head and Neck Squamous Cell Carcinoma

Evaluation of the antitumor potential of cerebrolysin

The GAL/GALR2 axis promotes the perineural invasion of salivary adenoid cystic carcinoma via epithelial‐to‐mesenchymal transition

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