Dear user, the application need JavaScript support. Please enable JavaScript in your browser.

You are browsing as a GUEST
Title of the item:

Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma.

Title :
Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma.
Authors :
Murakami, Tomohiro
Shoji, Yoshiaki
Nishi, Tomohiko
Chang, Shu‐Ching
Jachimowicz, Ron D.
Hoshimoto, Sojun
Ono, Shigeshi
Shiloh, Yosef
Takeuchi, Hiroya
Kitagawa, Yuko
Hoon, Dave S. B.
Bustos, Matias A.
Show more
Source :
Molecular Oncology; Apr2021, Vol. 15 Issue 4, p1069-1087, 19p
Academic Journal
Resistance to standard cisplatin‐based chemotherapies leads to worse survival outcomes for patients with esophageal squamous cell carcinoma (ESCC). Therefore, there is an urgent need to understand the aberrant mechanisms driving resistance in ESCC tumors. We hypothesized that ubiquilin‐4 (UBQLN4), a protein that targets ubiquitinated proteins to the proteasome, regulates the expression of Meiotic Recombination 11 Homolog A (MRE11A), a critical component of the MRN complex and DNA damage repair pathways. Initially, immunohistochemistry analysis was conducted in specimens from patients with ESCC (n = 120). In endoscopic core ESCC biopsies taken from 61 patients who underwent neoadjuvant chemotherapy (NAC) (5‐fluorouracil and cisplatin), low MRE11A and high UBQLN4 protein levels were associated with reduced pathological response to NAC (P < 0.001 and P < 0.001, respectively). Multivariable analysis of surgically resected ESCC tissues from 59 patients revealed low MRE11A and high UBLQN4 expression as independent factors that can predict shorter overall survival [P = 0.01, hazard ratio (HR) = 5.11, 95% confidence interval (CI), 1.45–18.03; P = 0.02, HR = 3.74, 95% CI, 1.19–11.76, respectively]. Suppression of MRE11A expression was associated with cisplatin resistance in ESCC cell lines. Additionally, MRE11A was found to be ubiquitinated after cisplatin treatment. We observed an amplification of UBQLN4 gene copy numbers and an increase in UBQLN4 protein levels in ESCC tissues. Binding of UBQLN4 to ubiquitinated‐MRE11A increased MRE11A degradation, thereby regulating MRE11A protein levels following DNA damage and promoting cisplatin resistance. In summary, MRE11A and UBQLN4 protein levels can serve as predictors for NAC response and as prognostic markers in ESCC patients. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Oncology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We use cookies to help identify your computer so we can tailor your user experience, track shopping basket contents and remember where you are in the order process.