Novel metastasis-related gene CIM functions in the regulation of multiple cellular stress-response pathways

Kiyoshi Yanagisawa, Hiroyuki Konishi, Chinatsu Arima, Shuta Tomida, Toshiyuki Takeuchi, Yukako Shimada, Yasushi Yatabe, Tetsuya Mitsudomi, Hirotaka Osada, Takashi Takahashi

研究成果: ジャーナルへの寄稿学術論文査読

24 被引用数 (Scopus)


Various stresses of the tumor microenvironment produced by insufficient nutrients, pH, and oxygen can contribute to the generation of altered metabolic and proliferative states that promote the survival of metastatic cells. Among many cellular stress-response pathways activated under such conditions are the hypoxia-inducible factor (HIF) pathway and the unfolded protein response (UPR), which is elicited as a response to endoplasmic reticulum (ER) stress. In this study, we report the identification of a novel cancer invasion and metastasis-related gene (hereafter referred to as CIM, also called ERLEC1), which influences both of these stress-response pathways to promote metastasis. CIM was identified by comparing the gene expression profile of a highly metastatic human lung cancer cell line with its weakly metastatic parental clone. We showed that CIM is critical for metastatic properties in this system. Proteomic approaches combined with bioinformatic analyses revealed that CIM has multifaceted roles in controlling the response to hypoxia and ER stress. Specifically, CIM sequestered OS-9 from the HIF-1a complex and PHD2, permitting HIF-1a accumulation by preventing its degradation. Ectopic expression of CIM in lung cancer cells increased their tolerance to hypoxia. CIM also modulated UPR through interaction with the key ER stress protein BiP, influencing cell proliferation under ER stress conditions. Our findings shed light on how tolerance to multiple cellular stresses at a metastatic site can be evoked by an integrated mechanism involving CIM, which can function to coordinate those responses in a manner that promotes metastatic cell survival.

ジャーナルCancer Research
出版ステータス出版済み - 01-12-2010

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究


「Novel metastasis-related gene CIM functions in the regulation of multiple cellular stress-response pathways」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。