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RAD18 may function as a predictor of response to preoperative concurrent chemoradiotherapy in patients with locally advanced rectal cancer through caspase-9-caspase-3-dependent apoptotic pathway.

ABSTRACT: Neoadjuvant chemoradiotherapy (nCRT) has been widely applied to improve the local control rate and survival rate in patients with locally advanced rectal cancer (LARC), yet only part of LARC patients would benefit from nCRT. Therefore, it is imperative to predict the therapeutic outcome of nCRT. Here, we showed that RAD18, an E3 ubiquitin-linked enzyme, played a fundamental role in predicting the response of LARC patients to nCRT. According to clinical data, patients with low RAD18 expression level in their pre-nCRT biopsies had a superior response to nCRT compared to those with high RAD18 expression. Inhibition of RAD18 expression in rectal cancer cells pronouncedly attenuated the proliferation and promoted apoptosis after exposing to irradiation or/and 5-fluorouracil (5-Fu). Downregulated RAD18 levels increased cell apoptosis by activating caspase-9-caspase-3-mediated apoptotic pathway, thus resulting in the enhancement of cell radiosensitivity and 5-Fu susceptibility. Furthermore, a xenograft nude mouse model showed that silencing RAD18 significantly slowed tumor growth after irradiation or/and 5-Fu in vivo. Collectively, these results implied that RAD18 could be a new biomarker to predict LARC patients who might benefit from nCRT and provide new strategies for clinical treatment of LARC.

SUBMITTER: Yan X

PROVIDER: S-EPMC6558645 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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RAD18 may function as a predictor of response to preoperative concurrent chemoradiotherapy in patients with locally advanced rectal cancer through caspase-9-caspase-3-dependent apoptotic pathway.

Yan Xueqi X Chen Jie J Meng You Y He Chao C Zou Shitao S Li Peng P Chen Ming M Wu Jinchang J Ding Wei-Qun WQ Zhou Jundong J

Cancer medicine 20190429 6

Neoadjuvant chemoradiotherapy (nCRT) has been widely applied to improve the local control rate and survival rate in patients with locally advanced rectal cancer (LARC), yet only part of LARC patients would benefit from nCRT. Therefore, it is imperative to predict the therapeutic outcome of nCRT. Here, we showed that RAD18, an E3 ubiquitin-linked enzyme, played a fundamental role in predicting the response of LARC patients to nCRT. According to clinical data, patients with low RAD18 expression le ...[more]

PMID: 31033216

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Project description:Background:Inflammatory response and nutritional status are associated with cancer development and progression. The purpose of this study was to explore whether the preoperative fibrinogen-albumin ratio index (FARI) is related to prognosis and chemoradiotherapy outcome of radical surgery after neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced rectal cancer (LARC). Methods:In total, 123 patients with LARC who underwent radical surgery after NCRT between June 2012 and December 2018 were collected in this study. Time-dependent receiver operating characteristic (ROC) curve analysis was made to evaluate the ability of the markers for forecasting prognosis. The correlation between FARI and clinicopathological parameters was analyzed. The Kaplan-Meier survival analysis, univariate and multivariate analysis based on Cox proportional hazards models, and subgroup analysis were performed to evaluate overall survival (OS) and disease-free survival (DFS). A nomogram was constructed to evaluate the predictive role of FARI in DFS. Results:The ROC curve analysis showed that the ability of FARI on DFS prediction was superior to those of other inflammatory markers and carcinoembryonic antigen (CEA) (P<0.05). Based on the Youden's index, the optimal cut-off value of FARI was 8.8%. High FARI patients (>8.8%) showed a poor response to NCRT and a decreased DFS rate (P<0.05). In addition, multivariate analysis revealed that FARI (HR=3.098, P=0.033), neutrophil-to-lymphocyte ratio (NLR), and postoperative T stage were independent prognostic factors for DFS in TNM stage III LARC patients. However, FARI failed to distinguish patients with poor OS. Harrell's concordance index (C-index) of the nomogram containing FARI (0.807) was obviously higher than that without it (0.732) among LARC patients who underwent radical surgery after NCRT. Moreover, multivariate analysis revealed FARI (OR=3.044, P=0.012) as an independent predictor for response to NCRT. Conclusion:Among LARC patients who underwent radical surgery after NCRT, preoperative FARI is an independent prognostic factor for DFS and an independent predictor for response to NCRT.

Project description:PurposeInduction chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy alone are both standard treatment regimens for managing locally advanced nasopharyngeal carcinoma. However, the results of comparisons between them in clinical trials vary. Therefore, we designed this meta-analysis to illustrate their advantages and disadvantages in patients with locally advanced nasopharyngeal carcinoma.MethodsWe thoroughly searched the PubMed, EMBASE, and Cochrane Library databases and then merged the effect indicators of hazard ratios and risk ratios using RevMan 5.1.ResultsSeven randomized controlled trials totaling 2,319 patients were included in our research. The synthesized results showed that induction chemotherapy plus concurrent chemoradiotherapy improved overall survival (HR = 0.75, 95% CI: 0.63-0.89, P = 0.001), progression-free survival (HR = 0.69, 95% CI: 0.60-0.80, P < 0.001), distant metastasis-free survival (HR = 0.65, 95% CI: 0.53-0.80, P < 0.001) and locoregional recurrence-free survival (HR = 0.68 95%, CI: 0.54-0.86, P = 0.001) versus concurrent chemoradiotherapy alone. It also increased the risk of anemia, thrombocytopenia, and neutropenia during concurrent chemoradiotherapy. However, the incidence of leukopenia and mucositis was similar in induction chemotherapy and induction chemotherapy plus concurrent chemoradiotherapy. Furthermore, the subgroup analysis showed better survival outcomes with induction chemotherapy plus concurrent chemoradiotherapy than with concurrent chemoradiotherapy alone in the triweekly cisplatin subgroup (all P < 0.01), whereas induction chemotherapy plus concurrent chemoradiotherapy could only improve progression-free survival and locoregional recurrence-free survival in the weekly cisplatin subgroup (HR = 0.78, P = 0.02; and HR = 0.66, P = 0.03, respectively).ConclusionsInduction chemotherapy plus concurrent chemoradiotherapy improved survival outcomes in patients with locally advanced nasopharyngeal carcinoma versus concurrent chemoradiotherapy. For the weekly cisplatin regimen subgroup, it did not improve remote control or overall survival versus concurrent chemoradiotherapy alone, warranting further clarification.

Dataset Information

RAD18 may function as a predictor of response to preoperative concurrent chemoradiotherapy in patients with locally advanced rectal cancer through caspase-9-caspase-3-dependent apoptotic pathway.

Publications

RAD18 may function as a predictor of response to preoperative concurrent chemoradiotherapy in patients with locally advanced rectal cancer through caspase-9-caspase-3-dependent apoptotic pathway.

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