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Leucine zipper tumor suppressor 2 inhibits cell proliferation and regulates Lef/Tcf-dependent transcription through Akt/GSK3? signaling pathway in lung cancer.

ABSTRACT: Leucine zipper tumor suppressor 2 (LZTS2) is implicated in several cancers; however, its biological mechanisms in non-small cell lung cancer (NSCLC) are not yet understood. We found that low levels of LZTS2 in NSCLC were correlated with tumor and nodal status. LZTS2 could inhibit cell proliferation and cell cycle transition at the G1/S phase and was implicated in the regulation of proteins associated with the canonical Wnt pathway, including GSK3? and ?-catenin through inactivating the Akt pathway. These results provide novel mechanistic insight into the biological roles of LZTS2 in lung cancer cells.

SUBMITTER: Cui QZ

PROVIDER: S-EPMC3753887 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other

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Leucine zipper tumor suppressor 2 inhibits cell proliferation and regulates Lef/Tcf-dependent transcription through Akt/GSK3β signaling pathway in lung cancer.

Cui Quan-Zhe QZ Tang Zhong-Ping ZP Zhang Xiu-Peng XP Zhao Huan-Yu HY Dong Qian-Ze QZ Xu Ke K Wang En-Hua EH

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20130612 9

Leucine zipper tumor suppressor 2 (LZTS2) is implicated in several cancers; however, its biological mechanisms in non-small cell lung cancer (NSCLC) are not yet understood. We found that low levels of LZTS2 in NSCLC were correlated with tumor and nodal status. LZTS2 could inhibit cell proliferation and cell cycle transition at the G1/S phase and was implicated in the regulation of proteins associated with the canonical Wnt pathway, including GSK3β and β-catenin through inactivating the Akt pathw ...[more]

PMID: 23761130

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Project description:Early in cancer development, tumour cells express vascular endothelial growth factor (VEGF), a secreted molecule that is important in all stages of angiogenesis, an essential process that provides nutrients and oxygen to the nascent tumor and thereby enhances tumor-cell survival and facilitates growth. Survivin, another protein involved in angiogenesis, is strongly expressed in most human cancers, where it promotes tumor survival by reducing apoptosis as well as favoring endothelial cell proliferation and migration. The mechanisms by which cancer cells induce VEGF expression and angiogenesis upon survivin up-regulation remain to be fully established. Since the PI3K/Akt signalling and ?-catenin-Tcf/Lef dependent transcription have been implicated in the expression of many cancer-related genes, including survivin and VEGF, we evaluated whether survivin may favor VEGF expression, release from tumor cells and induction of angiogenesis in a PI3K/Akt-?-catenin-Tcf/Lef-dependent manner. Here, we provide evidence linking survivin expression in tumor cells to increased ?-catenin protein levels, ?-catenin-Tcf/Lef transcriptional activity and expression of several target genes of this pathway, including survivin and VEGF, which accumulates in the culture medium. Alternatively, survivin downregulation reduced ?-catenin protein levels and ?-catenin-Tcf/Lef transcriptional activity. Also, using inhibitors of PI3K and the expression of dominant negative Akt, we show that survivin acts upstream in an amplification loop to promote VEGF expression. Moreover, survivin knock-down in B16F10 murine melanoma cells diminished the number of blood vessels and reduced VEGF expression in tumors formed in C57BL/6 mice. Finally, in the chick chorioallantoid membrane assay, survivin expression in tumor cells enhanced VEGF liberation and blood vessel formation. Importantly, the presence of neutralizing anti-VEGF antibodies precluded survivin-enhanced angiogenesis in this assay. These findings provide evidence for the existance of a posititve feedback loop connecting survivin expression in tumor cells to PI3K/Akt enhanced ?-catenin-Tcf/Lef-dependent transcription followed by secretion of VEGF and angiogenesis.

Dataset Information

Leucine zipper tumor suppressor 2 inhibits cell proliferation and regulates Lef/Tcf-dependent transcription through Akt/GSK3? signaling pathway in lung cancer.

Publications

Leucine zipper tumor suppressor 2 inhibits cell proliferation and regulates Lef/Tcf-dependent transcription through Akt/GSK3β signaling pathway in lung cancer.

Similar Datasets

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