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Cancer Med. 2019 Jun;8(6):3094-3104. doi: 10.1002/cam4.2203. Epub 2019 Apr 29.

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.

Author information

1
Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, PR China.
2
Department of Oncology, The Jiangyin Clinical College of Xuzhou Medical University, Wuxi, Jiangsu, P.R. China.
3
Department of Surgical Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, PR China.
4
Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA.

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.

KEYWORDS:

RAD18; apoptosis; locally advanced rectal cancer; neoadjuvant chemoradiotherapy

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