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FANCJ Expression Predicts the Response to 5-Fluorouracil-Based Chemotherapy in MLH1-Proficient Colorectal Cancer

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Fanconi anemia protein, FANCJ, directly interacts with MLH1, a key protein involved in DNA mismatch repair. Deficient mismatch repair, or microsatellite instability, is a potent marker for the ineffectiveness of 5-fluorouracil (5-FU) in colorectal cancer (CRC). We investigated the significance of FANCJ expression in CRC, focusing on the effects of 5-FU-based adjuvant chemotherapy.

Methods

Clinicopathologic features and immunohistochemical expression of FANCJ and MLH1 were studied in 219 patients with CRC. We also analyzed 5-FU sensitivity in CRC cell lines with varying levels of FANCJ expression.

Results

FANCJ expression was elevated in tumor tissues compared with normal epithelial tissue. High expression of FANCJ was significantly associated with 5-FU resistance measured by the SDI test (P < 0.05) and poor recurrence-free survival (RFS) (P < 0.05). Among patients with stage II/III tumors who received 5-FU, patients with tumors exhibiting high FANCJ expression had significantly worse RFS than did patients with tumors exhibiting low FANCJ expression (P < 0.01). Among patients who did not receive adjuvant chemotherapy, FANCJ expression was not correlated with RFS (P = 0.76). High FANCJ expression was correlated with 5-FU resistance in tumors with normal MLH1 expression (P < 0.05) but not in tumors not expressing MLH1 (P = 0.9). In vitro, FANCJ overexpression was correlated with 5-FU resistance in MLH1-proficient HCT116 3-6 cells but not in MLH1-deficient HCT116 cells.

Conclusions

FANCJ could be a useful biomarker to predict the response to 5-FU and prognosis of CRC, particularly in tumors with normal MLH1 expression.

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Acknowledgment

We thank Professor J. Patrick Barron, chairman of the Department of International Medical Communications of Tokyo Medical University for reviewing an earlier version of this manuscript. We also thank Prof. Richard C Boland for providing the HCT116 and HCT116 3-6 cells, Dr. Kazuaki Matsuoka (Taiho Pharmaceutical Co. Ltd.) for providing unpublished observation, and Ms. Naoko Katakura for technical support.

Disclosure

None of the authors have any competing financial interests related to this work.

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Authors and Affiliations

  1. Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Ryota Nakanishi MD, Hiroyuki Kitao PhD, Yoshihiko Fujinaka MD, Nami Yamashita MD & Makoto Iimori PhD

  2. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Ryota Nakanishi MD, Yoshihiko Fujinaka MD, Nami Yamashita MD, Eriko Tokunaga MD, PhD, Natsumi Yamashita MD, PhD, Masaru Morita MD, PhD, Yoshihiro Kakeji MD, PhD & Yoshihiko Maehara MD, PhD

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  1. Ryota Nakanishi MD
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Correspondence to Hiroyuki Kitao PhD.

Electronic supplementary material

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Supplementary material 1

Fig. S1 Immunohistochemistry and western blotting for FANCJ. a Positive control. Immunohistochemistry with primary antibodies obtained from Novus Biologicals (b) and Sigma (c). d Negative control. Western blotting of whole-cell extracts (e) and of cells with downregulated expression of FANCJ (f). FANCJ KD FANCJ knock-down (R1 636 kb)

Supplementary material 2

Fig. S2 Recurrence-free survival (RFS) of patients with stage II or III CRC according to FANCJ expression. a Patients with high or low expression of FANCJ. b Patients with high expression of FANCJ. c Patients with low expression of FANCJ. d Patients with stage II or III disease (R1 91 kb)

Supplementary material 3

Fig. S3 Immunohistochemistry for MLH1. a CRC specimen showing normal MLH1 expression. Insets show normal (A–N) and tumor (A–T). b Specimen showing abnormal MLH1 staining. MLH1 was normally expressed in normal epithelium (B–N) but not in tumor (B–T). Magnification, ×100 (a, b); ×400 (R1 835 kb)

Supplementary material 4

Fig. S4 FANCJ expression and 5-FU sensitivity in CRC cell lines. a Western blotting for FANCJ in CRC cell lines with normal or high level of FANCJ protein. b Relative score of IC50 to 5-FU of HCT116 and HCT116 3-6 cells. Data are shown as relative scores of IC50 to 5-FU, which was normalized by that of noninfected cells of each cell line as 1.00. Error bars represent standard errors. *P < 0.05. FANCJ OE FANCJ overexpression (R1 88 kb)

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Nakanishi, R., Kitao, H., Fujinaka, Y. et al. FANCJ Expression Predicts the Response to 5-Fluorouracil-Based Chemotherapy in MLH1-Proficient Colorectal Cancer. Ann Surg Oncol 19, 3627–3635 (2012). https://doi.org/10.1245/s10434-012-2349-8

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  • DOI: https://doi.org/10.1245/s10434-012-2349-8

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