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SOX4 transcriptionally regulates multiple SEMA3/plexin family members and promotes tumor growth in pancreatic cancer.

ABSTRACT: Semaphorin signaling through Plexin frequently participates in tumorigenesis and malignant progression in various types of cancer. In particular, the role of semaphorin signaling in pancreatic ductal adenocarcinoma (PDAC) remains unexplored, despite a high likelihood of metastasis and mortality. Unlike other epithelial malignancies that often express a small number of specific genes in the Semaphorin/Plexin family, five or more are often expressed in human PDAC. Such concomitant expression of these SEMA3/Plexin family members is not a result of gene amplification, but (at least partially) from increased gene transcription activated by SOX4 de novo expressed in PDAC. Via chromatin-immunoprecipitation, luciferase promoter activity assay and electrophoresis mobility shift assay, SOX4 is demonstrated to bind to the consensus site at the promoter of each SEMA3 and Plexin gene to enhance transcription activity. Conversely, RNAi-knockdown of SOX4 in PDAC cell lines results in decreased expression of SEMA3/Plexin family members and is associated with restricted tumor growth both in vitro and in SCID mice. We further demonstrate that SOX4 levels parallel with the summed expression of SEMA3/Plexin family members (P = 0.033, NPar Kruskal-Wallis one-way analysis), which also correlates with poor survival in human PDAC (P = 0.0409, Kaplan-Meier analysis). Intriguingly, miR-129-2 and miR-335, both of which target SOX4 for degradation, are co-repressed in human PDAC cases associated with up-regulated SOX4 in a statistically significant way. In conclusion, we disclose a miR-129-2(miR-335)/SOX4/Semaphorin-Plexin regulatory axis in the tumorigenesis of pancreatic cancer.

SUBMITTER: Huang HY

PROVIDER: S-EPMC3520963 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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SOX4 transcriptionally regulates multiple SEMA3/plexin family members and promotes tumor growth in pancreatic cancer.

Huang Hsin-Yi HY Cheng Yu-Yao YY Liao Wei-Chih WC Tien Yu-Wen YW Yang Chih-Hsin James CH Hsu Su-Ming SM Huang Pei-Hsin PH

PloS one 20121212 12

Semaphorin signaling through Plexin frequently participates in tumorigenesis and malignant progression in various types of cancer. In particular, the role of semaphorin signaling in pancreatic ductal adenocarcinoma (PDAC) remains unexplored, despite a high likelihood of metastasis and mortality. Unlike other epithelial malignancies that often express a small number of specific genes in the Semaphorin/Plexin family, five or more are often expressed in human PDAC. Such concomitant expression of th ...[more]

PMID: 23251334

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Project description:The Plexins family of proteins are well-characterized transmembrane receptors of semaphorins, axon guidance cue molecules, that mediate the cell attraction or repelling effects for such cues. Plexins and their ligands are involved in numerous cellular activities, such as motility, invasion, and adhesion to the basement membrane. The detachment of cells and the gain in motility and invasion are hallmarks of the cancer metastasis cascade, thus generating interest in exploring the role of plexins in cancer metastasis. Semaphorin-plexin complexes can act as tumor promoters or suppressors, depending upon the cancer type, and are under investigation for therapeutic purposes. Our group has identified Semaphorin-5A (SEMA5A)/Plexin-B3 as an attractive targetable complex for pancreatic cancer (PC) metastasis. However, our understanding of the Plexin-B3 function and pathological expression in PC is limited, and our present study delineates the role of Plexin-B3 in PC malignancy. We examined the pathological expression of Plexin-B3 in PC tumors and metastasis using a human tissue microarray, disease progression model of PDX-Cre-Kras(G12D) (KC) mice, and different metastatic sites obtained from the KrasG12D; Trp53R172H; Pdx1-Cre (KPC) mice model. We observed a higher Plexin-B3 expression in PC tumor cores than the normal pancreas, and different metastatic sites were positive for Plexin-B3 expression. However, in the KC mice model, the Plexin-B3 expression increased initially and then decreased with the disease progression. Next, to evaluate the functional role of Plexin-B3, we utilized T3M-4- and CD18/HPAF-Control and -Plexin B3 knockdown cells for different in vivo and in vitro studies. The knockdown of Plexin-B3 enhanced the in vitro cellular migration, invasiveness, and impaired colony formation in three-dimensional culture, along with an increase in cellular spread and remodeling of the actin filaments. We also observed a higher metastasis in nude mice injected with T3M-4- and CD18/HPAF-shPlexin-B3 cells compared to their respective control cells. Furthermore, we observed a lower number of proliferating Ki-67-positive cells and higher ALDH1-A1-positive cells in the tumors formed by Plexin-B3 knockdown cells compared to tumors formed by the control cells. Together, our data suggest that the loss of Plexin-B3 is associated with the interference of cell division machinery and the induction of stem cell-like characteristics in PC cells.

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SOX4 transcriptionally regulates multiple SEMA3/plexin family members and promotes tumor growth in pancreatic cancer.

Publications

SOX4 transcriptionally regulates multiple SEMA3/plexin family members and promotes tumor growth in pancreatic cancer.

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