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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States, and one of the ten most common cancers in Taiwan
To investigate whether SEMA3 or the related receptors (Plexin/ Neuropilin) are involved in the carcinogenesis of pancreatic cancers, immunohistochemistry was performed in 62 PDAC cases paired with normal pancreatic tissue
We investigated the possibility that co-expression of SEMA3/Plexin/NRP family members in PDACs is caused by the neo-expression of some master control gene(s) crucial for tumorigenesis of PDAC, possibly transcription factor(s) that could interact with a consensus DNA binding motif present in the promoter of each SEMA3/Plexin/NRP gene
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States, and one of the ten most common cancers in Taiwan. The poor prognosis of PDAC can be attributed to its aggressive biological behavior and its resistance to chemotherapy or radiotherapy, which necessitates a detailed mechanistic study of PDAC for therapeutic design [1]. Gene expression and genome-wide mutational studies indicate that human pancreatic cancer results from alteration of multiple genes that function through a core set of at least 12 cellular signaling pathways [2]. Through an analysis of more than 20000 transcripts, an average of 63 genetic alterations in pancreatic cancer has been demonstrated. The mechanisms for aberrant expression of each specific gene in pancreatic cancer are diverse, including point mutation, gene deletion, and amplification [2]
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