KCTD12 is negatively regulated by Kit in gastrointestinal stromal tumors
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Yoshiyuki Suehara1,*, Keisuke Akaike1,2,*, Kenta Mukaihara1,2, Aiko Kurisaki-Arakawa2, Daisuke Kubota1, Taketo Okubo1,2, Hiroyuki Mitomi2, Keiko Mitani2, Michiko Takahashi2, Midori Toda-Ishii1,2, Youngji Kim2, Yu Tanabe1, Tatsuya Takagi1, Takuo Hayashi2, Kaoru Mogushi3, Kazuo Kaneko1, Takashi Yao2 and Tsuyoshi Saito2
1Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan
2Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
3Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan
*These authors contributed equally to this work
Tsuyoshi Saito, email: firstname.lastname@example.org
Keywords: gastrointestinal stromal tumor; KIT; pfetin; mutation; tumor suppressor
Received: March 31, 2017 Accepted: April 28, 2018 Published: June 05, 2018
Our group has previously demonstrated that pfetin, encoded by the KCTD12 gene, is a strong prognostic biomarker for gastrointestinal stromal tumors (GISTs). However, the underlying mechanisms that control pfetin expression remain unknown. To elucidate the regulatory mechanisms of KCTD12 in GIST, in addition to a possible association between KCTD12 alterations and protein expression, we examined 76 patients with GISTs for KCTD12 mutations by PCR-direct sequence, and compared these results with clinicopathologic data. The function of pfetin in GIST progression was also revealed using GIST T1 cells. In this series, pfetin expression was not observed in 15 cases, and loss of pfetin expression was associated with higher mitotic rate (>5/50HPFs: p = 0.029). There was also a trend between presence of necrosis and loss of pfetin expression but this was not statistically significant (p = 0.09). KCTD12 mutations were frequently observed in 22 out of 76 GISTs (28.9%); however, they did not affect protein expression and were not associated with patients’ prognosis. KCTD12 in vitro knockdown resulted in the accelerated growth of GIST T1 cells, confirming that pfetin functions as a tumor suppressor. KIT knockdown significantly inhibited cellular growth and upregulated the expression of pfetin at both the mRNA and protein level. These findings suggest that GISTs with loss of pfetin expression has proliferative advantage and that higher pfetin expression in GISTs may be indicative of lower expression levels of KIT. This relationship confirms that pfetin is a useful prognostic marker in GISTs.
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