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NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/β-catenin pathway and Bcl-2 expression.

Chen J, Yang H, Wen J, Luo K, Liu Q, Huang Y, Zheng Y, Tan Z, Huang Q, Fu J - Oncotarget (2015)

Bottom Line: Our results showed that NHE9 prevented CRT-induced apoptosis.Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling.Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

ABSTRACT
Recently, we found that NHE9 mRNA was upregulated in chemoradiotherapy (CRT)-resistant esophageal squamous cell carcinoma (ESCC); however, the underlying mechanisms were unclear. Here, we aimed to clarify the functional contribution of NHE9 to CRT resistance, understand the molecular basis of NHE9-dependent resistance in ESCC, and identify potential therapeutic targets. Our results showed that NHE9 prevented CRT-induced apoptosis. Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling. Moreover, upregulated Bcl-2 protein was also observed in cells exhibiting NHE9-induced CRT resistance. A higher NHE9 level was associated with a poor response to CRT and less decrease in T and N stage in ESCC patients. Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression. Taken together, our findings demonstrate that NHE9 can be an effective predictor of CRT response and may be useful in the development of targeted therapies for CRT-resistant ESCC.

No MeSH data available.


Related in: MedlinePlus

the expression of NHE9 in ESCC tissuesESCC cases demonstrating negative, weak, moderate, and strong NHE9 IHC signals are shown in addition to a negative control A–E.
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Figure 8: the expression of NHE9 in ESCC tissuesESCC cases demonstrating negative, weak, moderate, and strong NHE9 IHC signals are shown in addition to a negative control A–E.

Mentions: An immunohistochemical assay was utilized to detect the expression of NHE9 in endoscopic biopsy samples before CRT. Results were obtained from 76 samples (samples could not be obtained from 26 patients, and inconclusive results were obtained from 3 slides). A total of 48 of the 76 patients showed strong positive staining (a score of 6–7), 22 patients showed moderate positive staining (a score of 3–5), and 6 patients showed weak positive staining (a score of 0–2). Positive immunoreactivity for NHE9 protein was mainly detected in the tumor cytoplasm; however, positive staining was also occasionally observed in the basal layer of the normal esophageal epithelium (Figure 8A–8D). Interestingly, strong positive staining was observed around microvessels, which might suggest a link between NHE9 and the tumor microenvironment.


NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/β-catenin pathway and Bcl-2 expression.

Chen J, Yang H, Wen J, Luo K, Liu Q, Huang Y, Zheng Y, Tan Z, Huang Q, Fu J - Oncotarget (2015)

the expression of NHE9 in ESCC tissuesESCC cases demonstrating negative, weak, moderate, and strong NHE9 IHC signals are shown in addition to a negative control A–E.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494947&req=5

Figure 8: the expression of NHE9 in ESCC tissuesESCC cases demonstrating negative, weak, moderate, and strong NHE9 IHC signals are shown in addition to a negative control A–E.
Mentions: An immunohistochemical assay was utilized to detect the expression of NHE9 in endoscopic biopsy samples before CRT. Results were obtained from 76 samples (samples could not be obtained from 26 patients, and inconclusive results were obtained from 3 slides). A total of 48 of the 76 patients showed strong positive staining (a score of 6–7), 22 patients showed moderate positive staining (a score of 3–5), and 6 patients showed weak positive staining (a score of 0–2). Positive immunoreactivity for NHE9 protein was mainly detected in the tumor cytoplasm; however, positive staining was also occasionally observed in the basal layer of the normal esophageal epithelium (Figure 8A–8D). Interestingly, strong positive staining was observed around microvessels, which might suggest a link between NHE9 and the tumor microenvironment.

Bottom Line: Our results showed that NHE9 prevented CRT-induced apoptosis.Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling.Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

ABSTRACT
Recently, we found that NHE9 mRNA was upregulated in chemoradiotherapy (CRT)-resistant esophageal squamous cell carcinoma (ESCC); however, the underlying mechanisms were unclear. Here, we aimed to clarify the functional contribution of NHE9 to CRT resistance, understand the molecular basis of NHE9-dependent resistance in ESCC, and identify potential therapeutic targets. Our results showed that NHE9 prevented CRT-induced apoptosis. Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling. Moreover, upregulated Bcl-2 protein was also observed in cells exhibiting NHE9-induced CRT resistance. A higher NHE9 level was associated with a poor response to CRT and less decrease in T and N stage in ESCC patients. Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression. Taken together, our findings demonstrate that NHE9 can be an effective predictor of CRT response and may be useful in the development of targeted therapies for CRT-resistant ESCC.

No MeSH data available.


Related in: MedlinePlus