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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

Representative pathological images of the xenograftHE staining of injected tumors confirmed the ESCC phenotype in both Eca109/NHE and Eca109/Con grafts. IHC staining for NHE9 showed that the expression of NHE9 was significantly higher in Eca109/NHE grafts. Phosphorylated Src and Bcl-2 were upregulated in resected Eca109/NHE xenografts, whereas their expression was largely inhibited after ABT-737 and Dasatinib treatments in both Eca109/NHE and Eca109/Con grafts.
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Figure 7: Representative pathological images of the xenograftHE staining of injected tumors confirmed the ESCC phenotype in both Eca109/NHE and Eca109/Con grafts. IHC staining for NHE9 showed that the expression of NHE9 was significantly higher in Eca109/NHE grafts. Phosphorylated Src and Bcl-2 were upregulated in resected Eca109/NHE xenografts, whereas their expression was largely inhibited after ABT-737 and Dasatinib treatments in both Eca109/NHE and Eca109/Con grafts.

Mentions: HE staining revealed a malignant phenotype, and IHC staining confirmed the expression of NHE9, phosphorylated Src, and Bcl-2. Histologic analysis revealed that tumor xenografts displayed the ESCC phenotype, and IHC staining showed increased expression of NHE9 in Eca109/NHE cells. Src phosphorylation and Bcl-2 expression were largely inhibited after treatment with Dasatinib and ABT-737 (Figure 7).


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)

Representative pathological images of the xenograftHE staining of injected tumors confirmed the ESCC phenotype in both Eca109/NHE and Eca109/Con grafts. IHC staining for NHE9 showed that the expression of NHE9 was significantly higher in Eca109/NHE grafts. Phosphorylated Src and Bcl-2 were upregulated in resected Eca109/NHE xenografts, whereas their expression was largely inhibited after ABT-737 and Dasatinib treatments in both Eca109/NHE and Eca109/Con grafts.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Representative pathological images of the xenograftHE staining of injected tumors confirmed the ESCC phenotype in both Eca109/NHE and Eca109/Con grafts. IHC staining for NHE9 showed that the expression of NHE9 was significantly higher in Eca109/NHE grafts. Phosphorylated Src and Bcl-2 were upregulated in resected Eca109/NHE xenografts, whereas their expression was largely inhibited after ABT-737 and Dasatinib treatments in both Eca109/NHE and Eca109/Con grafts.
Mentions: HE staining revealed a malignant phenotype, and IHC staining confirmed the expression of NHE9, phosphorylated Src, and Bcl-2. Histologic analysis revealed that tumor xenografts displayed the ESCC phenotype, and IHC staining showed increased expression of NHE9 in Eca109/NHE cells. Src phosphorylation and Bcl-2 expression were largely inhibited after treatment with Dasatinib and ABT-737 (Figure 7).

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