Annals of Surgical Oncology

, Volume 22, Issue 8, pp 2640–2648 | Cite as

Association of MicroRNA-31-5p with Clinical Efficacy of Anti-EGFR Therapy in Patients with Metastatic Colorectal Cancer

  • Hisayoshi Igarashi
  • Hiroyoshi Kurihara
  • Kei Mitsuhashi
  • Miki Ito
  • Hiroyuki Okuda
  • Shinichi Kanno
  • Takafumi Naito
  • Shinji Yoshii
  • Hiroaki Takahashi
  • Takaya Kusumi
  • Tadashi Hasegawa
  • Yasutaka Sukawa
  • Yasushi Adachi
  • Kenji Okita
  • Koichi Hirata
  • Yu Imamura
  • Yoshifumi Baba
  • Kohzoh Imai
  • Hiromu Suzuki
  • Hiroyuki Yamamoto
  • Katsuhiko NoshoEmail author
  • Yasuhisa Shinomura
Colorectal Cancer



Gene mutations in the pathway downstream of epidermal growth factor receptor (EGFR) are considered to induce resistance to anti-EGFR therapy in colorectal cancer (CRC). We recently reported that microRNA-31 (miR-31)-5p may regulate BRAF activation and play a role in the signaling pathway downstream of EGFR in CRC. Therefore, we hypothesized that miR-31-5p can be a useful biomarker for anti-EGFR therapy in CRC.


We evaluated miR-31-5p expression and gene mutations [KRAS (codon 61 or 146), NRAS (codon 12, 13, or 61), and BRAF (V600E)] in the EGFR downstream pathway in 102 CRC patients harboring KRAS (codon 12 or 13) wild-type who were treated with anti-EGFR therapeutics. Progression-free survival (PFS) and overall survival (OS) were evaluated.


KRAS (codon 61 or 146), NRAS, and BRAF mutations were detected in 6.9, 6.9, and 5.9 % patients, respectively. Compared with CRCs with at least one mutation (n = 20), significantly better PFS (P = 0.0003) but insignificantly better OS were observed in CRCs harboring all wild-type genes (KRAS, NRAS, and BRAF). High miR-31-5p expression was identified in 11 % (n = 11) patients and was significantly associated with shorter PFS (P = 0.003). In CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS (P = 0.027).


High miR-31-5p expression was associated with shorter PFS in patients with CRC treated with anti-EGFR therapeutics. Moreover, in CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS, suggesting that it may be a useful and additional prognostic biomarker for anti-EGFR therapy.


Overall Survival Epidermal Growth Factor Receptor BRAF Mutation Colon Cancer Cell Line Epidermal Growth Factor Receptor Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank the pathology departments of Sapporo Medical University Hospital and Keiyukai Sapporo Hospital for providing the tissue specimens. The authors also thank Enago ( for English language review. This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research [Grant Numbers: 23790800 (to K.N.) and 23390200 (to Y.S.)], A-STEP (Adaptable & Seamless, Technology Transfer Program through Target-driven R&D) (to K.N.), Sapporo Jikeikai Tomoiki Foundation (to K.N.), Takeda Science Foundation (to K.N.), and Daiwa Securities Health Foundation (to H.I.).



Supplementary material

10434_2014_4264_MOESM1_ESM.docx (50 kb)
Supplementary material 1 Supplementary Method (DOCX 49 kb)
10434_2014_4264_MOESM2_ESM.tif (78 kb)
Supplementary material 2 Supplementary Figure 1 The scatter diagram of relative expression levels of micorRNA-31-5p and -3p of 102 colorectal cancer (CRC) patients who received anti-EGFR therapy (TIFF 78 kb)
10434_2014_4264_MOESM3_ESM.tif (118 kb)
Supplementary material 3 Supplementary Figure 2. Kaplan–Meier survival curves of patients treated with anti-EGFR therapy according to the mutational status in KRAS, NRAS, and BRAF genes. (a) Overall survival (OS) of patients with at least one mutation in KRAS (codon 61 or 146) or NRAS (codon 12, 13, or 61) versus patients with all wild-type copies of the 2 genes. (b) OS of patients with mutation in BRAF versus patients with wild-type copies of BRAF. (c) OS of patients with at least one mutation in KRAS, NRAS, and BRAF versus all wild-type copies of the 3 genes. (TIFF 117 kb)
10434_2014_4264_MOESM4_ESM.tif (61 kb)
Supplementary material Supplementary Figure 3. Kaplan–Meier survival curves of patients treated with anti-EGFR therapy according to microRNA-31-5p expression. Overall survival of the high-expression group versus the low-expression group 4 (TIFF 60 kb)
10434_2014_4264_MOESM5_ESM.tif (89 kb)
Supplementary material Supplementary Figure 4. Kaplan–Meier survival curves of patients treated with anti-EGFR therapy according to microRNA-31-3p expression. (a) Progression-free survival and (b) overall survival of the high-expression group versus the low-expression group 5 (TIFF 88 kb)
10434_2014_4264_MOESM6_ESM.tif (44 kb)
Supplementary material 6 Supplementary Figure 5. The distribution of relative expression levels of miR-31-5p or -3p of colon cancer cell lines. (TIFF 44 kb)


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Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Hisayoshi Igarashi
    • 1
  • Hiroyoshi Kurihara
    • 1
  • Kei Mitsuhashi
    • 1
  • Miki Ito
    • 1
  • Hiroyuki Okuda
    • 2
  • Shinichi Kanno
    • 1
  • Takafumi Naito
    • 1
  • Shinji Yoshii
    • 3
    • 4
  • Hiroaki Takahashi
    • 3
  • Takaya Kusumi
    • 5
  • Tadashi Hasegawa
    • 6
  • Yasutaka Sukawa
    • 1
    • 7
  • Yasushi Adachi
    • 1
  • Kenji Okita
    • 8
  • Koichi Hirata
    • 8
  • Yu Imamura
    • 9
  • Yoshifumi Baba
    • 9
  • Kohzoh Imai
    • 10
  • Hiromu Suzuki
    • 11
  • Hiroyuki Yamamoto
    • 12
  • Katsuhiko Nosho
    • 1
    Email author
  • Yasuhisa Shinomura
    • 1
  1. 1.Department of Gastroenterology, Rheumatology and Clinical ImmunologySapporo Medical University School of MedicineSapporoJapan
  2. 2.Department of OncologyKeiyukai Sapporo HospitalSapporoJapan
  3. 3.Department of GastroenterologyKeiyukai Sapporo HospitalSapporoJapan
  4. 4.Department of GastroenterologyNTT East Sapporo HospitalSapporoJapan
  5. 5.Department of SurgeryKeiyukai Sapporo HospitalSapporoJapan
  6. 6.Department of PathologySapporo Medical University School of MedicineSapporoJapan
  7. 7.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  8. 8.Department of Surgery, Surgical Oncology and ScienceSapporo Medical University School of MedicineSapporoJapan
  9. 9.Department of Gastroenterological Surgery, Graduate School of Medical ScienceKumamoto UniversityKumamotoJapan
  10. 10.Division of Cancer Research, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  11. 11.Department of Molecular BiologySapporo Medical University School of MedicineSapporoJapan
  12. 12.Division of Gastroenterology and Hepatology, Department of Internal MedicineSt. Marianna University School of MedicineKawasakiJapan

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