(500) TMEM127 May Downregulate Receptor Tyrosine Kinases to Prevent Tumorigenesis

Introduction: TMEM127 is a paraganglioma tumor suppressor gene of unknown function, and mutant tumors show a molecular profile of activated kinase signaling, suggesting that it may function by antagonizing receptor tyrosine kinases (RTK). To gather insights into TMEM127 function in vivo, we previously generated a recombinant mouse lacking Tmem127 under a generic promoter (Tmem127 CMV-KO), and here analyzed the abundance of RTKs in adrenal gland, thyroid and liver.

Methods: Experiments presented in this study were performed in April 2022, and the thyroid experiments began in January 2023. Standard dissection techniques were used to remove the liver (n=6), adrenal glands (n=6), and thyroids (n=5) from adult male and female WT and Tmem127 KO mice. Whole cell lysates were prepared for Western Blot Analysis. The blots were probed for β-Actin or 𝜶-tubulin (loading control), Tmem127, EGFR, HER2, FGFR, and PDGFR-⍺, total ERK, and p-ERK and levels were quantified relative to control using ImageJ.

Results: Our preliminary results showed that adrenal glands from Tmem127 KO mice have increased FGFR (1.5-fold) and PDGFR-𝜶 (3.7-fold) levels relative to WT mice. Liver from Tmem127 KO mice also showed higher levels of PDGFR-𝜶 (5-fold). Thyroids from Tmem127 KO mice expressed more RET than WT mice (3.4-fold, p< 0.05), with a trend toward increase in phosphorylation of the downstream target p-ERK.

Conclusions: Our preliminary data suggest that Tmem127 likely acts as a broad regulator of RTKs with roles in human oncogenesis, and this could explain its mechanism as a tumor suppressor. On-going experiments include expanding our cohort size and age range, RTK spectrum, and examining their activation level by measuring phosphorylated RTK and downstream signaling molecules. Future studies will explore the mechanism of TMEM127 action.