Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis

Abstract

Abstract. Pancreatic cancer is one of the most aggressive and devastating malignancies. The Hedgehog (Hh) pathway has been reported to play an important role in pancreatic cancer development and progression. The aim of this study was to examine the activation of the Hh pathway in human pancreatic cancer tissue samples and pancreatic cancer cell lines, and the molecular mechanisms involved in the Hh pathway mediated effects on pancreatic cancer cell proliferation and invasion. The expression levels of Hh molecules in human pancreatic cancer tissue samples and pancreatic cancer cell lines were evaluated using RT-PCR. The role of the Hh pathway in cell proliferation and invasion was evaluated using flow cytometry, MTT, colony formation assays and Transwell invasion assays, and the expression of cancer stem cell markers and epithelial-mesenchymal transition (EMT) were evaluated using flow cytometry and RT-PCR. Tumorigenicity assays were used to further investigate the role of the Hh pathway in vivo. Hh molecules were highly expressed in human pancreatic cancer tissue samples and pancreatic cancer cell lines. Inhibition of the Hh pathway notably decreased cell proliferation and induced apoptosis through inhibition of the PI3K/AKT pathway and cancer stem cells. Furthermore, inhibition of the Hh signaling pathway significantly inhibited EMT by suppressing the activation of transcription factors Snail and Slug, which are correlated with significantly reduced pancreatic cancer cell invasion, suggesting that the Hh signaling pathway is involved in early metastasis. These results indicate that activation of the Hh pathway is a common event. Inhibition of the Hh pathway may be a potential molecular target of new therapeutic strategies for pancreatic cancer.

Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma

“…The present study posed and verified the hypothesis that the hedgehog signaling pathway activates the PI3K/AKT pathway, which subsequently upregulates the expression of MMP-2 and MMP-9 at the mRNA and protein level, thereby mediating GBM migration and invasion. The hedgehog signaling pathway has a vital role in the control of cell differentiation, cell proliferation and embryonic development (5,7,12). According to recent studies, aberrant activation of hedgehog signaling is linked to the aggressiveness of multiple tumor types, including GBM (21,22).…”

“…The hedgehog signaling pathway is essential for embryonic patterning and cancer development (5)(6)(7). The hedgehog protein family includes desert hedgehog, Indian hedgehog and sonic hedgehog (SHH).…”

“…Among them, SHH is the most widely expressed and the most potent protein. Once SHH binds to its receptor Patched 1, the transmembrane protein Smoothened is released, causing the transport of the transcription factor glioma-associated oncogene (Gli) into the nucleus, where it regulates the transcription of target genes that control cell differentiation, survival and growth (5,6). Three Gli genes (Gli1, Gli2 and Gli3) have been identified in mammalian tissues, among which Gli1 is considered to be the only loyal marker of hedgehog pathway activity (8)(9)(10) studies have shown that the hedgehog pathway is associated with the migration and invasion of ovarian, pancreatic, esophageal and gastric carcinomas (6,(11)(12)(13).…”

Stem Cells in Pancreatic Cancer

“…Many studies showed that Shh signaling can activate pancreatic stellate cells, promotes fibroblast infiltration, and increases secretion of fibronectin, collagen type I, MMPs, and TGF-β [62]. Studies in the pancreatic cancer cell line PANC-1 showed that inhibition of Hedgehog signaling by Smoothened (Smo) suppression can reverse EMT, induce apoptosis via PI3K/AKT inhibition, and inhibit the invasion of pancreatic cancer cells [63]. Moreover, combination of focal irradiation with Hedgehog signaling inhibition reduces lymph node metastasis in an orthotopic animal model [64].…”

A sesquiterpene lactone from Siegesbeckia glabrescens suppresses Hedgehog/Gli-mediated transcription in pancreatic cancer cells

“…Despite research efforts, there has been limited progress regarding the treatment of this disease; therefore, novel strategies to identify new therapeutic agents are urgently required. The Hedgehog (Hh) signaling pathway is critical for morphogenesis signaling and is inappropriately activated in patients with pancreatic cancer (2,3). In addition, this pathway is associated with the growth and metastasis of various types of tumors, including pancreatic cancer (4,5).…”