title: Significant correlation between LKB1 and LGR5 gene expression and the association with poor recurrence-free survival in rectal cancer after preoperative chemoradiotherapy.
abstract: OBJECTIVE
  The aim of the present study was to investigate whether the gene expression levels of LKB1 and LGR5 correlated with clinical outcome in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy (CRT).
  
  
  METHODS
  Residual cancer cells were obtained from 52 patients with locally advanced rectal cancer treated with preoperative CRT. Total RNA was then isolated from formalin-fixed, paraffin-embedded specimens using microdissection. The expression levels of LKB1 and LGR5 genes were measured using real-time reverse-transcription polymerase chain reaction and by immunohistochemistry. In addition, in vitro studies were performed using colon cancer cell lines to study the serial changes of LKB1, LGR5 and PRKAA1 (AMPK) gene expression levels after irradiation.
  
  
  RESULTS
  Our data demonstrate that specimens obtained from patients with poor pathological response and tumor recurrence had significantly higher gene expression levels of LKB1 and LGR5 than those without them (P < 0.05), and there was a significant positive correlation between LKB1 and LGR5 gene expression after CRT (Spearman's ρ: 0.429, P = 0.0023). The patients with high expression levels of both LKB1 and LGR5 had a significantly lower recurrence-free survival compared with the other group (P = 0.0055, 95 % confidence interval: 1.39-11.08). Lastly, in vitro studies demonstrated a similar pattern of serial gene expression among LKB1, LGR5 and PRKAA1 after irradiation.
  
  
  CONCLUSIONS
  Our results suggest that LKB1 and LGR5 expression may be implicated in resistance to CRT, therefore contributing to tumor relapse in patients with locally advanced rectal cancer treated with preoperative CRT.
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. saigusa@clin.medic.mie-u.ac.jp
authors.forename: Susumu
authors.initials: S
authors.lastname: Saigusa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Inoue
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Toiyama
authors.forename: Mikio
authors.initials: M
authors.lastname: Kawamura
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Okugawa
authors.forename: Masato
authors.initials: M
authors.lastname: Okigami
authors.forename: Junichiro
authors.initials: J
authors.lastname: Hiro
authors.forename: Keiichi
authors.initials: K
authors.lastname: Uchida
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Mohri
authors.forename: Masato
authors.initials: M
authors.lastname: Kusunoki
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012004:Rectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D012189:Retrospective Studies; D018401:Sample Size
chemical_list: D014408:Biomarkers, Tumor; C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human