VICKZ1 enhances tumor progression and metastasis in lung adenocarcinomas in mice

Yifat Bar Zakay Rosenfeld, Miriam Krumbein, Avner Yeffet, Nathan Schiffmann, Inbal Mishalian, Eli Pikarsky, Froma Oberman, Zvi Fridlender, Joel K. Yisraeli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The VICKZ (Igf2bp) family of RNA binding proteins regulate RNA function at many levels, including intracellular RNA localization, RNA stability, and translational control. One or more of the three VICKZ paralogs are upregulated in many different types of cancers. Here, we show how VICKZ1 enhances, and dominant negative VICKZ1 inhibits, cell migration, growth in soft agar, and wound healing in a mouse lung adenocarcinoma cell line containing a constitutively active, mutant Kras. Similarly, modulation of VICKZ1 activity promotes or inhibits metastases upon implantation of these cells into syngeneic mice. To test these effects in a genetic model system, we generated a mouse with an inducible VICKZ1 transgene and found that isolated overexpression of VICKZ1 in the lungs had no noticeable effect on morphology. Although directed overexpression of mutant Kras in the lungs led to the formation of small adenomas, concurrent overexpression of VICKZ1 remarkably accelerated tumor growth and formation of pulmonary adenocarcinomas. VICKZ1-containing ribonucleoprotein complexes are highly enriched in Kras mRNA in lung adenocarcinoma cells, and Kras signaling is enhanced in these cells by overexpression of VICKZ1. Analysis of lung carcinoma patients reveals that elevated VICKZ1 expression correlates with lower overall survival; this reduction is dramatically enhanced in those patients bearing a mutant Kras gene. Our study reveals that RNA binding proteins of the VICKZ family can synergize with Kras to influence signaling and oncogenic activity.

Original languageAmerican English
Pages (from-to)4169-4181
Number of pages13
JournalOncogene
Volume38
Issue number21
DOIs
StatePublished - 23 May 2019

Bibliographical note

Funding Information:
Funding This research was supported by the Israel Science Foundation, the Israel Cancer Research Fund, and the Eliahu Penn Foundation (JKY).

Publisher Copyright:
© 2019, Springer Nature Limited.

Keywords

  • Igf2bp1
  • RNA binding protein
  • cell migration
  • transgenic mouse
  • tumor progression

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