Project 3: Tumor suppressive functions of LZTFL1

Human LZTFL1 is located in the chromosome region 3p21.3, a hotspot for tumor suppressor genes. To understand the biological functions of LZTFL1, we surveyed the expression level of LZTFL1 in tumor and normal samples in tissue microarrays and a clinical archive of 84 gastric cancer specimens.

We found that LZTFL1 is expressed highly in the epithelial cells of normal tissues and is significantly downregulated in the corresponding tumor samples. The expression level of LZTFL1 correlated significantly with the survival outcomes of the patients and had significant inverse correlation with tumor metastasis. Overexpression of LZTFL1 in tumor cells inhibited anchorage-independent cell growth and cell migration in vitro and repressed tumor growth in vivo.

Furthermore, we showed that LZTFL1 expression is upregulated upon epithelial cell differentiation and is graded along the crypt-villus axis of the intestine, with weakest expression level in the proliferative zone of the crypt and highest expression level at the apex of the differentiation zone in the villus. Our results indicate that LZTFL1 is a tumor suppressor and that loss of LZTFL1 expression has significant clinical outcomes. LZTFL1 expression may serve as an independent prognostic marker for survival outcome of gastric cancer patients (Wei et al., Cancer Research. 2010).

Allelic loss and genetic alterations at chromosomal region 3p21.3 occur early and frequently in lung cancers. A homozygous 5 bp deletion in LZTFL1 coding sequence was identified recently in a consanguineous family diagnosed with Bardet-Biedl syndrome with situs inversus and insertional polydactyly (Marion et al., J Med Genet. 2012). LZTFL1 was also shown to regulate ciliary trafficking of the BBSome and Smoothened (Seo et al., PLoS Genet. 2011).

In collaboration with Drs. John Minna and Boning Gao at UT Southwestern, we found that LZTFL1 is expressed specifically in ciliated bronchial epithelial cells. We are currently testing whether the inhibitory effect of LZTFL1 on lung tumorigenesis is mediated through its suppressive function on Shh signaling pathway in vivo.