Abstract
KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that 18F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased 18F-FDG accumulation. Methods: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured 18F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in 18F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1α (HIF-1α), and maximum standardized uptake value with 51 clinical CRC samples. Results: In the in vitro experiments, 18F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and 18F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1α was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1α resulted in higher GLUT1 expression and 18F-FDG accumulation. In addition, HIF-1α knockdown decreased 18F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo 18F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1α and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1α and with maximum standardized uptake value. Conclusion: Mutated KRAS caused higher 18F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1α additively increased 18F-FDG accumulation in hypoxic lesions. 18F-FDG PET might be useful for predicting the KRAS status noninvasively.
| Original language | English |
|---|---|
| Pages (from-to) | 2038-2044 |
| Number of pages | 7 |
| Journal | Journal of Nuclear Medicine |
| Volume | 55 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 1 2014 |
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All Science Journal Classification (ASJC) codes
- Radiology Nuclear Medicine and imaging
Cite this
Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS. / Iwamoto, Masayoshi; Kawada, Kenji; Nakamoto, Yuji; Itatani, Yoshiro; Inamoto, Susumu; Toda, Kosuke; Kimura, Hiroyuki; Sasazuki, Takehiko; Shirasawa, Senji; Okuyama, Hiroaki; Inoue, Masahiro; Hasegawa, Suguru; Togashi, Kaori; Sakai, Yoshiharu.
In: Journal of Nuclear Medicine, Vol. 55, No. 12, 01.12.2014, p. 2038-2044.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS
AU - Iwamoto, Masayoshi
AU - Kawada, Kenji
AU - Nakamoto, Yuji
AU - Itatani, Yoshiro
AU - Inamoto, Susumu
AU - Toda, Kosuke
AU - Kimura, Hiroyuki
AU - Sasazuki, Takehiko
AU - Shirasawa, Senji
AU - Okuyama, Hiroaki
AU - Inoue, Masahiro
AU - Hasegawa, Suguru
AU - Togashi, Kaori
AU - Sakai, Yoshiharu
PY - 2014/12/1
Y1 - 2014/12/1
N2 - KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that 18F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased 18F-FDG accumulation. Methods: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured 18F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in 18F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1α (HIF-1α), and maximum standardized uptake value with 51 clinical CRC samples. Results: In the in vitro experiments, 18F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and 18F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1α was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1α resulted in higher GLUT1 expression and 18F-FDG accumulation. In addition, HIF-1α knockdown decreased 18F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo 18F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1α and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1α and with maximum standardized uptake value. Conclusion: Mutated KRAS caused higher 18F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1α additively increased 18F-FDG accumulation in hypoxic lesions. 18F-FDG PET might be useful for predicting the KRAS status noninvasively.
AB - KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that 18F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased 18F-FDG accumulation. Methods: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured 18F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in 18F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1α (HIF-1α), and maximum standardized uptake value with 51 clinical CRC samples. Results: In the in vitro experiments, 18F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and 18F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1α was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1α resulted in higher GLUT1 expression and 18F-FDG accumulation. In addition, HIF-1α knockdown decreased 18F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo 18F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1α and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1α and with maximum standardized uptake value. Conclusion: Mutated KRAS caused higher 18F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1α additively increased 18F-FDG accumulation in hypoxic lesions. 18F-FDG PET might be useful for predicting the KRAS status noninvasively.
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U2 - 10.2967/jnumed.114.142927
DO - 10.2967/jnumed.114.142927
M3 - Article
VL - 55
SP - 2038
EP - 2044
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
SN - 0161-5505
IS - 12
ER -