AIM: To analyze the expression of retinoic acid receptor responder 3 (RARRES3) protein in paraffin-embedded tissues of hepatocellular carcinoma (HCC) and cholangiocarcinoma(CC), and the correlation of RARRES3 producti...AIM: To analyze the expression of retinoic acid receptor responder 3 (RARRES3) protein in paraffin-embedded tissues of hepatocellular carcinoma (HCC) and cholangiocarcinoma(CC), and the correlation of RARRES3 production with tumor differentiation.METHODS: Expression of RARRES3 in tissues from 21CC (10 well-, 7 moderately- and 4 poorly-differentiated)and 32 HCC was determined by immunohistochemistry.RESULTS: Among 21 CC tissues, RARRES3 was detected in 8 (80%) of 10 well-differentiated tumors. Only 2 (18.2%)out of 11 tumors with moderate or poor differentiation showed positive RARRES3 expression. RARRES3 expression in well-differentiated CC was significantly higher than that in tumors with moderate or poor differentiation (Fisher exact test, P＜0.01). Expression of RARRES3 was not different between early (Ⅰ and Ⅱ) and late (Ⅲ and Ⅳ) stages of CC.Among 30 HCC tissues, 17 (56.7%) weakly expressed RARRES3 in HCC cells, and 25 (83.3%) normal tissues adjacent to HCC expressed the protein. RARRES3 expression was significantly decreased in HCC tissues compared to that in adjacent normal tissues (logistic regression analysis, OR = 0.27, 95% CI (0.11-0.62), P＜0.01).CONCLUSION: Expression of RARRES3 is positively correlated to well-differentiated CC, which supports the role of RARRES3 in malignant epithelial differentiation of the tumor. The decrease in RARRES3 expression in tissues of HCC and CC with moderate and poor differentiation suggests that altered RARRES3 expression may play a role in the carcinogenesis of the liver and biliary tract.展开更多
Retinoic acid receptor responder 3(RARRES3)has been characterized as a tumor suppressor in multiple types of cancer.This study aimed to examine the expression profile of RARRES3 across the PAM50 subtypes of breast can...Retinoic acid receptor responder 3(RARRES3)has been characterized as a tumor suppressor in multiple types of cancer.This study aimed to examine the expression profile of RARRES3 across the PAM50 subtypes of breast cancer.The DNA methylation status of RARRES3 was checked in the basal-like subtype,and the underlying mechanisms of its dysregulation were explored.RNA-sequencing(seq)and methylation data from The Cancer Genome Atlas were used for in-silico analysis.Basal-like representative SUM149 and MDA-MB-468 cell lines were used for in vitro and in vivo studies.Compared to tumor-adjacent normal tissues,only the basal-like tumor tissues had significantly downregulated RARRES3 expression.The methylation level of four CpG sites in the promoter region showed a strong negative correlation with RARRES3 expression.The gene coding for DNA methyltransferase 3A(DNMT3A)had consistent positive correlations with the methylation of the CpG sites.Chromatin Immunoprecipitation-quantitative polymerase chain-reaction and bisulfite sequencing PCR showed that DNMT3A could bind to the promoter region of RARRES3 and promote methylation of the CpG sites within the region.DNMT3A knockdown significantly restored RARRES3 expression at the mRNA and protein level in the two cell lines.CCK-8,colony formation,and flow cytometric analysis showed that RARRES3 overexpression attenuated the growth-promoting effects of DNMT3A overexpression and also weakened the DNMT3A overexpression-induced activation of ERK1/2 and PI3K/AKT signaling.In summary,this study revealed that DNMT3A enhances promoter methylation of the RARRES3 gene and suppresses its transcription in basal-like breast cancer.The DNMT3A-RARRES3 signaling pathway might be a potential target for the treatment of this tumor subtype.展开更多
基金Supported by the Tri-Service General Hospital (TSGH-C91-14),Department of Defense (N91079)National Science Council (NSC91-2314-B016-108) Taipei, Taiwan, China
文摘AIM: To analyze the expression of retinoic acid receptor responder 3 (RARRES3) protein in paraffin-embedded tissues of hepatocellular carcinoma (HCC) and cholangiocarcinoma(CC), and the correlation of RARRES3 production with tumor differentiation.METHODS: Expression of RARRES3 in tissues from 21CC (10 well-, 7 moderately- and 4 poorly-differentiated)and 32 HCC was determined by immunohistochemistry.RESULTS: Among 21 CC tissues, RARRES3 was detected in 8 (80%) of 10 well-differentiated tumors. Only 2 (18.2%)out of 11 tumors with moderate or poor differentiation showed positive RARRES3 expression. RARRES3 expression in well-differentiated CC was significantly higher than that in tumors with moderate or poor differentiation (Fisher exact test, P＜0.01). Expression of RARRES3 was not different between early (Ⅰ and Ⅱ) and late (Ⅲ and Ⅳ) stages of CC.Among 30 HCC tissues, 17 (56.7%) weakly expressed RARRES3 in HCC cells, and 25 (83.3%) normal tissues adjacent to HCC expressed the protein. RARRES3 expression was significantly decreased in HCC tissues compared to that in adjacent normal tissues (logistic regression analysis, OR = 0.27, 95% CI (0.11-0.62), P＜0.01).CONCLUSION: Expression of RARRES3 is positively correlated to well-differentiated CC, which supports the role of RARRES3 in malignant epithelial differentiation of the tumor. The decrease in RARRES3 expression in tissues of HCC and CC with moderate and poor differentiation suggests that altered RARRES3 expression may play a role in the carcinogenesis of the liver and biliary tract.
基金supported by the Science&Technology Department of Sichuan Province,China(2022YFS0314).
文摘Retinoic acid receptor responder 3(RARRES3)has been characterized as a tumor suppressor in multiple types of cancer.This study aimed to examine the expression profile of RARRES3 across the PAM50 subtypes of breast cancer.The DNA methylation status of RARRES3 was checked in the basal-like subtype,and the underlying mechanisms of its dysregulation were explored.RNA-sequencing(seq)and methylation data from The Cancer Genome Atlas were used for in-silico analysis.Basal-like representative SUM149 and MDA-MB-468 cell lines were used for in vitro and in vivo studies.Compared to tumor-adjacent normal tissues,only the basal-like tumor tissues had significantly downregulated RARRES3 expression.The methylation level of four CpG sites in the promoter region showed a strong negative correlation with RARRES3 expression.The gene coding for DNA methyltransferase 3A(DNMT3A)had consistent positive correlations with the methylation of the CpG sites.Chromatin Immunoprecipitation-quantitative polymerase chain-reaction and bisulfite sequencing PCR showed that DNMT3A could bind to the promoter region of RARRES3 and promote methylation of the CpG sites within the region.DNMT3A knockdown significantly restored RARRES3 expression at the mRNA and protein level in the two cell lines.CCK-8,colony formation,and flow cytometric analysis showed that RARRES3 overexpression attenuated the growth-promoting effects of DNMT3A overexpression and also weakened the DNMT3A overexpression-induced activation of ERK1/2 and PI3K/AKT signaling.In summary,this study revealed that DNMT3A enhances promoter methylation of the RARRES3 gene and suppresses its transcription in basal-like breast cancer.The DNMT3A-RARRES3 signaling pathway might be a potential target for the treatment of this tumor subtype.
