RORα and REV-ERBα are Associated With Clinicopathological Parameters and are Independent Biomarkers of Prognosis in Gastric Cancer

Wang, Xiaoshan; Jia, Ru; Chen, Ke; Wang, Jingjing; Jiang, Kai; Wang, Zhengguang

doi:10.1177/15330338211039670

Cited by 11 publications

(9 citation statements)

References 24 publications

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“…In agreement with the present study, Wang et al (2021) reported that GC patients with high RORα expression levels had the best prognosis [56]. Furthermore, low RORα expression in HCC has been associated with shorter overall and disease-free survival [34].…”

Section: Discussionsupporting

confidence: 92%

Gastric Carcinoma with low ROR alpha, low E- Cadherin and High LAPTM4B Immunohistochemical Profile; is associated with poor prognosis in Egyptian patients

Mashad

Kandil

Talab

et al. 2022

Preprint

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Background Gastric carcinoma (GC) is the tenth most prevalent cancer in both sexes in Egypt. Many pathways have been investigated regarding pathogenesis of GC, including epithelial-mesenchymal transition (EMT) pathway. In view of multiplicity of carcinogenic pathways, poor survival and chemotherapy resistance detected in GC patients, more analysis of these pathways is required for better molecular selection of patients, prediction of prognosis and developing new therapeutic targets. Down-regulation of E-Cadherin is an important EMT stage. RORα is a tumor suppressor gene, expressed in normal epithelial tissues and reduced in a variety of human cancers. Knocking down of RORα; increase cell proliferation, EMT, migration, and invasion. LAPTM4B is a protooncogene and it has been suggested to be strictly associated with EMT induction. Therefore, this work aims to investigate the role of RORα, LAPTM4B and E-Cadherin and its relationship to prognosis of GC. Methods This is a retrospective study where the standard immunohistochemical technique was done to assess the expression of RORα, LAPTM4B and E-Cadherin in 167 cases of chronic gastritis (control group) and 73 primary gastric carcinomas (51 of them have available adjacent non tumor tissue). Results Low RORα and high LAPTM4B expression in GC cases were associated with unfavorable prognostic factors such as positive lymph nodes, and high tumor budding. E-Cadherin Heterogeneous staining was associated with poor prognostic pathological criteria, such as diffuse type GC and high tumor budding. In GC, there was significant co parallel correlation between RORα and E-Cadherin expression while LAPTM4B showed inverse correlation with E-Cadherin expression. Low RORα, high LAPTM4B, and negative or heterogeneous E-Cadherin were the most common immunohistochemical profile in GC cases. Low RORα expression showed poor prognostic impact on overall patient survival. Conclusions Low RORα H-score and increased expression of LAPTM4B were significantly associated with unfavorable prognostic parameters of GC which may indicate their crucial role in tumor aggressiveness. The predominance of low RORα, high LAPTM4B and heterogeneous or negative E-Cadherin immunohistochemical profile in GC cases with unfavorable pathological parameters suggested that this profile may predict tumor behavior and this profile could be linked to EMT molecular subtype of GC

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Section: Discussionsupporting

confidence: 92%

Gastric Carcinoma with low ROR alpha, low E- Cadherin and High LAPTM4B Immunohistochemical Profile; is associated with poor prognosis in Egyptian patients

Mashad

Kandil

Talab

et al. 2022

Preprint

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“…RORα has been recognized as a tumor suppressor in many tumors [ 6 ]. Reduced RORα expression has been shown to positively correlate with clinical progression, metastasis [ 18 , 19 ], and shorter overall survival in GC [ 19 ], whereas, GC patients with higher RORα expression levels have a better prognosis [ 19 ], and AMP-activated protein kinase activator could bring about GC cell apoptosis by increasing RORα expression and activity [ 18 ], prompting that RORα may be a potential target for prevention and therapy in GC. In this study, our results showed that DADS induced G2/M phase arrest, accompanied by increased RORα expression in GC cells.…”

Section: Discussionmentioning

confidence: 99%

Diallyl disulfide inhibits proliferation, epithelial—mesenchymal transition, and invasion through RORα-mediated downregulation of Wnt1/β-catenin pathway in gastric cancer cells

Su¹,

He²,

Li³

et al. 2022

Journal of Food and Drug Analysis

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Overactivation of Wnt/β-catenin pathway due to dysfunction of retinoid-related orphan receptor α (RORα) is related to cancer development and progression. Diallyl disulfide (DADS), an active component of garlic, has been reported in our previous study for upregulation of RORα expression in gastric cancer (GC) cells. It remains to be elucidated the role and mechanism of RORα in DADS against GC. This study revealed that DADS treatment resulted in reduced expression levels of Wnt1, β-catenin, TCF-4, intranuclear β-catenin and p-β-catenin in GC cells, concomitant with the compromised expression of β-catenin target genes (Axin, c-Jun, and c-Myc). RORα overexpression augmented DADS-induced downregulation of Wnt1/β-catenin pathway, G2/M phase arrest, and cell growth inhibition in vitro and in vivo . Contrarily, knockdown of RORα attenuated these effects of DADS. Interestingly, DADS induced an increase in the binding of RORα to β-catenin, which may lead to reduction of β-catenin phosphorylation and nuclear translocation. This interplay modulated by DADS may affect β-catenin target gene expression for that the opposite results were observed in DADS-treated RORα knockdown and overexpression cells. DADS caused a decrease in vimentin, snail and MMP-9, as well as an increase in E-cadherin and TIMP3 expression, which restricted epithelial–mesenchymal transition (EMT), migration, and invasion. The aforementioned effects of DADS were weakened simultaneously when the suppression of DADS on the Wnt1/β-catenin pathway was resisted by knockdown of RORα. In contrast, overexpression of RORα enhanced the effects of DADS. Therefore, RORα-mediated downregulation of Wnt1/β-catenin pathway could undertake an important role in anticancer activity of DADS against GC cell proliferation, EMT, migration, and invasion.

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“…Te role of Rev-erbα in the development of gastric cancer will be demonstrated using KO mice in future. Further study is warranted to determine the mechanisms of reduced Nr1d1 gene expression in gastric cancer [12,13]. Rev-erbα can undergo various protein modifcations through ubiquitination/proteasome-dependent degradation pathways that afect its stability.…”

Section: Discussionmentioning

confidence: 99%

“…The role of Rev-erb α in the development of gastric cancer will be demonstrated using KO mice in future. Further study is warranted to determine the mechanisms of reduced Nr1d1 gene expression in gastric cancer [ 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

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Posttranslational Modifications of Rev-Erbα Protein and Abnormal Inflammatory Response in Gastric Cancer

Chen

Cheng

Wan

et al. 2022

Journal of Oncology

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We reported that Rev-erbα, a transcriptional repressor, is reduced in human gastric cancer and that it inhibits glycolysis in cultured gastric cancer cells. However, it is unclear whether Rev-erbα undergoes posttranslational modifications in gastric cancer. Here, we determined levels of Rev-erbα and its posttranslational modifications including phosphorylation, SUMOylation, and ubiquitination in N-methyl-N-nitrosourea (MNU)/Helicobacter pylori (H. pylori)-induced gastric cancer in mice and in cultured human gastric cancer cells. Administration of MNU plus H. pylori infection successfully induced gastric tumor in C57BL/6J mice. MNU/H. pylori decreased the levels of Rev-erbα in gastric tumor tissues of mice accompanied by an increase in the level of lactic acid. Rev-erbα protein SUMOylation and ubiquitination modifications were significantly increased, whereas phosphorylation was unchanged, in gastric cancer cells line BGC-823 and MNU/H. pylori-induced mouse gastric cancer tissues. Using human gastric cancer tissues, we found that Rev-erbα was specifically reduced in mucosal epithelial cells in gastric tissue. Cytokine levels were increased in MNU/H. pylori-exposed mice compared with control mice. Similarly, the levels of IL-6 IL-10, TNF-α, and VEGF were higher in the BGC-823 cell line compared with GES-1 cells. IL-6 and IL-1 incubation did not affect Rev-erbα levels in BGC-823 cells. Furthermore, Rev-erbα was recruited on the promoters of these cytokine genes, which suppressed their expression. Conclusively, Rev-erbα SUMOylation and subsequent ubiquitination may contribute to its protein reduction, which leads to increased glycolysis and abnormal inflammatory responses during the development of gastric cancer. Targeting Rev-erbα and its SUMOylation represents promising approaches for prevention and management of gastric cancer.

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RORα and REV-ERBα are Associated With Clinicopathological Parameters and are Independent Biomarkers of Prognosis in Gastric Cancer

Cited by 11 publications

References 24 publications

Gastric Carcinoma with low ROR alpha, low E- Cadherin and High LAPTM4B Immunohistochemical Profile; is associated with poor prognosis in Egyptian patients

Gastric Carcinoma with low ROR alpha, low E- Cadherin and High LAPTM4B Immunohistochemical Profile; is associated with poor prognosis in Egyptian patients

Diallyl disulfide inhibits proliferation, epithelial—mesenchymal transition, and invasion through RORα-mediated downregulation of Wnt1/β-catenin pathway in gastric cancer cells

Posttranslational Modifications of Rev-Erbα Protein and Abnormal Inflammatory Response in Gastric Cancer

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