title: The unfolded protein response regulator GRP78 is a novel predictive biomarker in colorectal cancer.
abstract: Adjuvant fluoropyrimidine-based (5-FU) chemotherapy is a mainstay of treatment for colorectal cancer (CRC), but only provides benefit for a subset of patients. To improve stratification we examined (for the first time in CRC), whether analysis of GRP78 expression provides a predictive biomarker and performed functional studies to examine the role of GRP78 in sensitivity to 5-FU. 396 CRC patient samples were collected in a prospective uniform manner and GRP78 expression was determined by immunohistochemistry on tissue microarrays using a well-validated antibody. Expression was correlated with clinicopathological parameters and survival. The role of GRP78 in 5-FU sensitivity was examined in CRC cells using siRNA, drug inhibition and flow cytometry. GRP78 expression was significantly elevated in cancer tissue (p < 0.0001), and correlated with depth of invasion (p = 0.029) and stage (p = 0.032). Increased overall 5-year survival was associated with high GRP78 expression (p = 0.036). Patients with stage II cancers treated by surgery alone, with high GRP78 also had improved survival (71% v 50%; p = 0.032). Stage III patients with high GRP78 showed significant benefit from adjuvant chemotherapy (52% vs. 28%; p = 0.026), whereas patients with low GRP78 failed to benefit (28% vs. 32%; p = 0.805). Low GRP78 was an independent prognostic indicator of reduced overall 5-year survival (p = 0.004; HR = 1.551; 95%CI 1.155-2.082). In vitro, inhibition of GRP78 reduces apoptosis in response to 5-FU in p53 wild-type cells. GRP78 expression may provide a simple additional risk stratification to inform the adjuvant treatment of CRC and future studies should combine analysis with determination of p53 status.
authors: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, L3 9TA, United Kingdom.
authors: Michael
authors: M
authors: Thornton
authors: Mohammed A
authors: MA
authors: Aslam
authors: Elizabeth M
authors: EM
authors: Tweedle
authors: Chin
authors: C
authors: Ang
authors: Fiona
authors: F
authors: Campbell
authors: Richard
authors: R
authors: Jackson
authors: Eithne
authors: E
authors: Costello
authors: Paul S
authors: PS
authors: Rooney
authors: Nikolina
authors: N
authors: Vlatković
authors: Mark T
authors: MT
authors: Boyd
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000032:analysis; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000032:analysis / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D056811:Unfolded Protein Response
chemical_list: D014408:Biomarkers, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005472:Fluorouracil
keywords: GRP78; biological markers; colorectal neoplasms; retrospective studies; tumour suppressor protein p53; unfolded protein response