PSMB8 as a Candidate Marker of Responsiveness to Preoperative Radiotherapy in Rectal Cancer Patients

Publication date: Available online 22 March 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ye J. Ha, Ka H. Tak, Chan W. Kim, Seon A. Roh, Eun K. Choi, Dong H. Cho, Jeong H. Kim, Seon K. Kim, Seon Y. Kim, Yong S. Kim, Jin C. Kim
PurposeThe ability to predict individual responsiveness to cancer therapy is urgently needed. This is particularly true for patients with locally advanced rectal cancer (LARC), as a large proportion are resistant to preoperative chemoradiotherapy (CRT). In this study, we sought to identify markers that could predict response by comparing the gene expression profiles of the tumors of patients who went on preoperative CRT.Methods and MaterialsThe basal gene expression profiles of tumors from 22 LARC patients who were responders (n=9) and non-responders (n=13) to preoperative CRT were analyzed using RNA sequencing (RNA-Seq). To validate the RNA-Seq findings, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was performed on tumor samples from an additional 40 LARC patients (n=20 responders; n=20 non-responders). Candidate genes were stably overexpressed or knocked down in colorectal cancer (CRC) cell lines, and the effect on response to radiation was tested in vitro, and in vivo in a mouse xenograft model.ResultsEight differentially expressed (>16-fold) genes (B3GALT4, HSPA1B, KRBOX1, PPBP, PPP1R18, PSMB8, SLC39A7, and TAP2) associated with the preoperative CRT response were identified (p<0.0005). Among these genes, real-time RT-PCR showed that PSMB8 and SLC39A7 were upregulated in the responsive group of the additional 40 LARC patients. In CRC cell lines, PSMB8 overexpression significantly reduced colony formation and increased the apoptosis-inducing molecules cleaved caspase-3 and cleaved PARP after 6 Gy irradiation. PSMB8 knockdown increased colony formation and decreased caspase-3 activation and cleaved PARP levels after irradiation. SLC39A7 overexpression had no significant effects on irradiated CSC cells. After irradiation of the xenografted mice, tumors that arose from CRC cell line HCT116 overexpressing PSMB8 grew more slowly than those from HCT116 with vector alone.ConclusionThese results suggest that PSMB8 is a predictive marker of preoperative radiosensitivity in LARC patients. Clinical validation in a larger cohort is now required.

Teaser

Preoperative chemoradiotherapy (CRT) has been widely used as the treatment of choice for locally advanced rectal cancer (LARC). Our aim was to identify the predictive markers for individual responsiveness to preoperative CRT in patients with LARC using RNA-Seq technology and to validate these findings via real-time RT-PCR and biological indicators. We identified the expression signatures of LARC with different radiosensitivity and proposed that PSMB8 could be a useful biomarker for predicting responsiveness of preoperative CRT.


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