Molecular marker identification for relapse prediction in 5-FU-based adjuvant chemotherapy in gastric and colorectal cancers.
To confirm the clinical significance of NF-κB and JNK protein expression from experimentally identified candidates for predicting prognosis for patients with 5-FU treatment, we evaluated the protein expression of surgically removed specimens. A total of 79 specimens were obtained from 30 gastric and 49 colorectal cancer patients who underwent R0 resection followed by postoperative 5-FU based adjuvant chemotherapy. Immunohistochemical examinations of NF-κB and JNK on tissue microarrays (TMAs) revealed that significantly shorter time-to-relapse (TTR) in both NF-κB(+) and JNK(-) subgroups in both gastric (NF-κB(+), p = 0.0002, HR11.7. 95%CI3 3.2-43.4; JNK(-), p = 0.0302, HR4.4, 95%CI 1.2-16.6) and colon (NF-κB(+), p = 0.0038, HR36.9, 95%CI 3.2-426.0; JNK(-), p = 0.0098, HR3.2, 95%CI 1.3-7.7) cancers. These protein expression patterns also show strong discriminately power in gastric cancer patients for overall survival rate, suggesting a potential utility as prognostic or chemosensitivity markers. Baseline expression of these proteins using gastric cancer cell lines demonstrated the reciprocal patterns between NF-κB and JNK, while 5-FU exposure of these cell lines only induced NF-κB, suggesting that NF-κB plays a dominant role in the response to 5-FU. Subsequent siRNA experiments confirmed that gene knockdown of NF-κB increased 5-FU-specific sensitivity, whereas that of JNK did not affect the chemosensitivity. These results suggest that the expression of these proteins may aid in the decisions involved with adjuvant chemotherapy for gastrointestinal tract cancers.
Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
Kazushige
K
Ishida
Satoshi S
SS
Nishizuka
Takehiro
T
Chiba
Miyuki
M
Ikeda
Kohei
K
Kume
Fumitaka
F
Endo
Hirokatsu
H
Katagiri
Teppei
T
Matsuo
Hironobu
H
Noda
Takeshi
T
Iwaya
Noriyuki
N
Yamada
Hisataka
H
Fujiwara
Masanori
M
Takahashi
Tetsuya
T
Itabashi
Noriyuki
N
Uesugi
Chihaya
C
Maesawa
Gen
G
Tamura
Tamotsu
T
Sugai
Koki
K
Otsuka
Keisuke
K
Koeda
Go
G
Wakabayashi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant / Q000379:methods*; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D034741:RNA, Small Interfering / Q000378:metabolism; D012008:Recurrence; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D048670:MAP Kinase Kinase 4; D005472:Fluorouracil