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. 2018 Mar;7(3):698-706.
doi: 10.1002/cam4.1361. Epub 2018 Feb 14.

Protein Phosphatase 2A (PP2A) Inhibitor CIP2A Indicates Resistance to Radiotherapy in Rectal Cancer

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Free PMC article

Protein Phosphatase 2A (PP2A) Inhibitor CIP2A Indicates Resistance to Radiotherapy in Rectal Cancer

Eva-Maria Birkman et al. Cancer Med. .
Free PMC article

Abstract

Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low-CIP2A-expressing tumors had more frequently moderate or excellent response to long-course (C)RT than patients with high-CIP2A-expressing tumors. They also had higher 36-month disease-specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long-course (C)RT in rectal cancer patients.

Keywords: Cancerous inhibitor of protein phosphatase 2A; chemoradiotherapy; rectal cancer.

Figures

Figure 1
Figure 1
Different CIP2A immunohistochemical cytoplasmic staining intensities in rectal adenocarcinomas. (A) Negative for CIP2A protein expression. (B) Weak (1 + ) CIP2A protein expression. (C) Moderate (2 + ) CIP2A protein expression. (D) Strong (3 + ) CIP2A protein expression. Original objective magnification 20x.
Figure 2
Figure 2
(A) The cell survival curves from the irradiation experiments show the mean surviving fraction ±SE for each radiation dose. The RKO cells treated with CIP2A siRNA (black) were more sensitive to radiation (mean AUC 1.7 ± 0.1 Gy) than the control cells treated with scrambled siRNA (gray) (mean AUC 2.1 ± 0.1 Gy; paired t‐test, = 0.015). (B) The corresponding Western blot demonstrates the reduction in CIP2A protein expression in siRNA‐treated cells (siCIP2A) in comparison with scrambled siRNA‐treated cells (siSCR) and nontreated control cells (contr). GADPH was used as a loading control.

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