Expression levels of hnRNP K and p21WAF1/CIP1 are associated with resistance to radiochemotherapy independent of p53 pathway activation in rectal adenocarcinoma

Daskalaki,Wassiliki; Wardelmann,Eva; Port,Matthias; Stock,Katharina; Steinestel,Julie; Huss,Sebastian; Sperveslage,Jan; Steinestel,Konrad; Eder,Stefan

doi:10.3892/ijmm.2018.3898

Expression levels of hnRNP K and p21WAF1/CIP1 are associated with resistance to radiochemotherapy independent of p53 pathway activation in rectal adenocarcinoma

Authors:
- Wassiliki Daskalaki
- Eva Wardelmann
- Matthias Port
- Katharina Stock
- Julie Steinestel
- Sebastian Huss
- Jan Sperveslage
- Konrad Steinestel
- Stefan Eder
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Affiliations: Gerhard‑Domagk‑Institute of Pathology, University Hospital Münster, D‑48149 Münster, Germany, Gerhard‑Domagk‑Institute of Pathology, University Hospital Münster, D‑48149 Münster, Germany, Bundeswehr Institute of Radiobiology Affiliated to The University of Ulm, D‑80937 Munich, Germany, Department of Urology, University Hospital Münster, D‑48149 Münster, Germany
Published online on: September 25, 2018 https://doi.org/10.3892/ijmm.2018.3898
Pages: 3269-3277
Copyright: © Daskalaki et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ionizing radiation (IR) is frequently applied in the treatment of rectal adenocarcinoma, however, there is marked variance in the response to radiochemotherapy between individual tumors. In our previous investigations, it was shown that the overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) confers radioresistance to malignant melanoma and colorectal carcinoma (CRC) in vitro, however, the underlying mechanism remains to be elucidated. As hnRNP K, a p53 binding partner and cofactor for the transcriptional activation of p53 target genes, is overexpressed in CRC, the present study investigated the possible radioprotective effect of the hnRNP K/p53‑induced upregulation of p21 (also known as WAF1/CIP1) in rectal adenocarcinoma. Immunohistochemistry was performed for hnRNP K, p53 and p21 in a series of 68 consecutive cases of rectal adenocarcinoma with full molecular characterization following radiochemotherapy and 14 corresponding pre‑therapeutic biopsies, and the results were correlated with clinicopathological characteristics and the percentage of vital tumor cells following therapy. In addition, pathway analyses, protein immunoprecipitation, western immunoblotting and immunofluorescence microscopy were performed to identify dysregulated kinase signaling and hnRNP K targets upon exposure of CRC cells to IR. Although the fraction of vital tumor cells upon neoadjuvant therapy was significantly higher in hnRNP K/p21‑positive tumors (P=0.0047 and P=0.0223, Students' t‑test), no significant association was found between the protein expression levels of hnRNP K, p53 and p21 (P>0.05, χ2 test). Irradiation enhanced apoptotic pathway activation via p53/CHK2 phosphorylation and poly (ADP‑ribose) polymerase cleavage, and induced the overexpression and interaction of hnRNP K and p53. However, p53 Ser15‑phosphorylation was independent of the presence of hnRNP K, and there was no measurable effect of hnRNP K on the expression of p21 in vitro. Taken together, the results of the present study support a radioprotective role for hnRNP K, which may be mediated through an interaction with p53, however, this effect appears to be independent of the hnRNP K/p53‑induced upregulation of p21 in rectal adenocarcinoma.

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