肝癌耐药和转移的凶手:胆碱酯酶α
  • 对9例肝细胞癌(HCC)和配对癌旁组织进行全外显子组和转录组分析,120例术后配对标本行组织芯片分析,48例配对标本行qRT-PCR等分析,细胞株行移植瘤等研究;
  • HCC组织中胆碱激酶α(CHKA)信使RNA水平升高,与CHKA位点扩增相关;
  • 稳定过表达CHKA的HCC细胞株转移和侵袭水平更高,移植瘤更大转移灶更多,CHKA高表达患者术后生存期更短;
  • CHKA过表达促进HCC侵袭性,对EGFR抑制剂产生耐药,通过促进EGFR和mTORC2相互作用而促进转移。
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Gastroenterology [IF:22.682]

Choline Kinase α Mediates Interactions Between the Epidermal Growth Factor Receptor and Mechanistic Target of Rapamycin Complex 2 in Hepatocellular Carcinoma Cells to Promote Drug Resistance and Xenograft Tumor Progression

胆碱激酶α介导肝癌细胞中表皮生长因子受体与mTORC2相互作用促进耐药和移植瘤进展

10.1053/j.gastro.2016.12.033

2017-01-05, Article

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BACKGROUND & AIMS: Choline kinase α (CHKA) catalyzes conversion of choline to phosphocholine and can contribute to carcinogenesis. Little is known about the role of CHKA in the pathogenesis of hepatocellular carcinoma (HCC).
METHODS: We performed whole-exome and transcriptome sequence analyses of 9 paired HCC and non-tumor-adjacent tissues. We performed tissue chip analyses of 120 primary HCC and non-tumor-adjacent tissues from patients who received surgery in Shanghai, China from January 2006 through December 2009; 48 sets of specimens (HCC and non-tumor-adjacent tissues) were also analyzed. CHKA gene copy number was quantified and findings were validated by quantitative reverse transcription polymerase chain reaction analysis. CHKA messenger RNA and protein levels were determined by polymerase chain reaction, immunohistochemical, and immunoblot analyses. CHKA was examined in 2 hepatocyte cell lines and 7 HCC-derived cell lines, and knocked down with small interfering RNAs in 3 HCC cell lines. Cells were analyzed in proliferation, wound healing, migration, and invasion assays. Cells were injected into tail veins of mice and tumor growth and metastasis were quantified. Immunoprecipitation and immunofluorescence assays were conducted to determine interactions between CHKA and the epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin complex 2.
RESULTS: Levels of CHKA messenger RNA were frequently increased in HCC tissues compared with nontumor tissues; increased expression was associated with amplification at the CHKA loci. Tumors that expressed high levels of CHKA had more aggressive phenotypes, and patients with these tumors had shorter survival times after surgery compared to patients whose tumors expressed low levels of CHKA. HCC cell lines that stably overexpressed CHKA had higher levels of migration and invasion than control HCC cells, and formed larger xenograft tumors with more metastases in mice compared to HCC cells that did not overexpress CHKA. CHKA was required for physical interaction between EGFR and mechanistic target of rapamycin complex 2. This complex was required for HCC cells to form metastatic xenograft tumors in mice and to become resistant to EGFR inhibitors.
CONCLUSIONS: We found levels of CHKA to be increased in human HCCs compared to nontumor tissues, and increased expression to be associated with tumor aggressiveness and reduced survival times of patients. Overexpression of CHKA in HCC cell lines increased their invasiveness, resistance to EGFR inhibitors, and ability to form metastatic tumors in mice by promoting interaction of EGFR with mechanistic target of rapamycin complex 2.

First Authors:
Xi-Meng Lin, Liang Hu, Jin Gu, Ruo-Yu Wang

Correspondence Authors:
Hong-Yang Wang,Lei Chen

All Authors:
Xi-Meng Lin,Liang Hu,Jin Gu,Ruo-Yu Wang,Liang Li,Jing Tang,Bao-Hua Zhang,Xing-Zhou Yan,Yan-Jing Zhu,Cong-Li Hu,Wei-Ping Zhou,Shao Li,Jing-Feng Liu,Frank J Gonzalez,Meng-Chao Wu,Hong-Yang Wang,Lei Chen

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