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.
Highlights
It is clear that neoadjuvant chemora diotherapy (CRT) can improve the outcome of esophageal squamous cell carcinoma (ESCC) [1, 2]
We examined the expression of NHE9 in ten ESCC cell lines (Fig. S1), and we selected Eca109 and KYSE30, which have relatively low levels of intrinsic NHE9, to establish stable overexpression lines (Eca109/NHE9 and KYSE30/NHE9)
The effect of NHE9 on apoptosisrelated pathways was tested by western blotting, and the results revealed that NHE9 could inhibit CRT-induced apoptosis
Summary
It is clear that neoadjuvant chemora diotherapy (CRT) can improve the outcome of esophageal squamous cell carcinoma (ESCC) [1, 2]. Only responders benefit from CRT, whereas nonresponders may suffer a worse prognosis [3, 4]. It is very important to explore the key markers and relevant subcellular processes affecting the CRT response. We previously conducted a microarray study using mRNA extracted from tumor tissue obtained from ESCC patents via endoscopic biopsy before CRT to examine differences in gene expression between responders and nonresponders [5]. It is possible that NHE9 is involved in regulating the response of ESCC to CRT; this requires further investigation
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