Id1 and Id3 genes confer poor prognosis in KRAS-mutant (KM) lung adenocarcinoma (LA) patients. Gene silencing reduces metastatic rate to the liver and increases survival

Background

Inhibitor of differentiation 1 (Id1) and 3 (Id3) genes confer poor prognosis being involved in LA spreading to the liver. KM may constitute a poor prognosis and a pro-metastatic feature. Here we study Id genes' role in KM LA and liver metastasis (LM).

Methods

424 LA patients were studied to assess the survival impact of Id1 and Id3 mRNA levels depending on KRAS status. The KM human LA cell line H1792-TGL-604 was used to address the impact of Id1 and Id3 genes on tumor cell proliferation and migration. A murine model of LM from LA was generated using immunocompromised mice by tumor cells intrasplenic injection. shRNA silencing was used to determine the impact of Idgenes. Two groups of mice inoculated with shRNA-Id1 and shRNA-Id1-Id3 tumor cells, were compared to those inoculated with twildtype (WT) cell line. FDG-PET was used to monitor LM. The effect of tumor cells genotype in the overall survival (OS) of the animals was also studied.

Results

Id1 and Id3 mRNA higher tumor levels predicted a shorter OS among patients with KM but not in KRAS-wildtype LA (p = 0.02 and p = 0.03, respectively). In vitro, the proliferation rate of cells silenced for Id1 and Id1/Id3 genes was 20.1% CI95% (0.17, 0.23) and 31% CI95% (0.245, 0.37), compared to 60.1% CI95% (0.54, 0.67), in the WT cell line (p 

Conclusions

Higher Id1 and Id3 mRNA tumor levels predicted a shorter OS in a large series of KM LA patients. Id1 and Id1/Id3 silencing in human KM tumor cells of LA decreased and delayed LM development in an in vivo model

Clinical trial identification

Legal entity responsible for the study

Clinica Universidad de Navarra

Funding

Ministerio de Economía y Competitividad. Instituto de Salud Carlos III. Gobierno de España.

Disclosure

All authors have declared no conflicts of interest.