Expression of CREB3L1 blocks key cancer pathways and suppresses metastasis of lung squamous cell carcinoma cells

Lung cancer is the leading cause of death due to cancer, with higher mortality rates than cancers of the colon, breast and prostate combined. About one quarter of lung cancers are lung squamous cell carcinomas (LUSC), with a five-year survival rate of only 16%. We discovered that the majority of LUSCs have reduced expression of a key transcription factor CREB3L1 (cAMP responsive element binding protein 3 like 1), known to function as a metastasis suppressor in breast, bladder and ovarian cancers. In this report, we set out to determine if CREB3L1 functions as a metastasis suppressor in LUSCs. A differential gene expression analysis showed that ectopic expression of CREB3L1 in NCI-H2170 and NCI-1703 cells caused significant reductions in many signaling pathway genes involved in promoting cell viability, survival, migration and angiogenesis. Expression of CREB3L1 was able to reduce cell migration and anchorage-independent growth in soft agar in NCI-H2170, NCI-H1703 and NCI-H226 LUSC cells. Expression of CREB3L1 had less impact on the growth of primary xenograft tumors for NCI-H2170 and NCI-H1703 cells, the latter of which formed atypical masses filled with blood. In contrast, xenografts of NCI-H226 expressing CREB3L1 showed significant reductions in primary tumor growth. Finally, in a mouse metastasis assay, expression of CREB3L1 in NCI-H2170 cells significantly reduced the formation of liver metastases and in NCI-H226 cells, lung metastases, as compared to their respective CREB3L1-deficient parental LUSC cells. Taken together, these results strongly support a role for CREB3L1 as a metastasis suppressor in lung squamous cell carcinoma cells.