Identification of a microRNA expression signature for chemoradiosensitivity of colorectal cancer cells, involving miRNAs-320a, -224, -132 and let7g.
OBJECTIVE
Preoperative chemoradiotherapy (CRT) represents the standard treatment for locally advanced rectal cancer. Tumor response and progression vary considerably. MicroRNAs represent master regulators of gene expression, and may therefore contribute to this diversity.


METHODS
Genome-wide microRNA (miRNA) profiling was performed for 12 colorectal cancer (CRC) cell lines and an individual in vitro signature of chemoradiosensitivity was established. Functional relevance of selected miRNAs was established by transfecting miRNA-mimics into SW480 and SW837 cells. The prognostic value of selected miRNAs was assessed in 128 pretherapeutic patient biopsies.


RESULTS
Thirty-six miRNAs were identified to significantly correlate with sensitivity to CRT (Q < 0.05) including miR-320a and other miRNAs involved in the MAPK-, TGF- and Wnt-pathway. Transfection of selected miRNAs (let-7g, miR-132, miR-224, miR-320a) each induced a shift of sensitivity. High expression of let-7 g was associated with a good prognosis in rectal cancer patients (P = 0.03).


CONCLUSIONS
This is the first report of a miRNA expression signature for in vitro chemoradiosensitivity of CRC cell lines. Many of the identified miRNAs have not been linked to the response to CRT and may represent potential molecular targets to sensitize resistant cancers. If further validated, let7g expression may serve as predictive biomarker.
Department of General and Visceral Surgery, University Medical Center Göttingen, Germany.
Junius
J
Salendo
Melanie
M
Spitzner
Frank
F
Kramer
Xin
X
Zhang
Peter
P
Jo
Hendrik A
HA
Wolff
Julia
J
Kitz
Silke
S
Kaulfuß
Tim
T
Beißbarth
Matthias
M
Dobbelstein
Michael
M
Ghadimi
Marian
M
Grade
Jochen
J
Gaedcke
D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction
C547077:MIRN132 microRNA, human; C546140:MIRN224 microRNA, human; C572916:MIRN320 microRNA, human; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human
MiR320; MiRNA; Preoperative chemoradiotherapy; Rectal cancer; let-7g