SCF, Regulated by HIF-1α, Promotes Pancreatic Ductal Adenocarcinoma Cell Progression

Abstract

Stem cell factor (SCF) and hypoxia-inducible factor-1α (HIF-1α) both have important functions in pancreatic ductal adenocarcinoma (PDAC). This study aims to analyze the expression and clinicopathological significance of SCF and HIF-1α in PDAC specimens and explore the molecular mechanism at PDAC cells in vitro and in vivo. We showed that the expression of SCF was significantly correlated with HIF-1α expression via Western blot, PCR, chromatin immunoprecipitation (ChIP) assay, and luciferase assay analysis. The SCF level was also correlated with lymph node metastasis and the pathological tumor node metastasis (pTNM) stage in PDAC samples. The SCF higher-expression group had significantly lower survival rates than the SCF lower-expression group (p<0.05). Hypoxia up-regulated the expression of SCF through the hypoxia-inducible factor (HIF)-1α in PDAC cells at the protein and RNA levels. When HIF-1α was knocked down by RNA interference, the SCF level decreased significantly. Additionally, ChIP and luciferase results demonstrated that HIF-1α can directly bind to the hypoxia response element (HRE) region of the SCF promoter and activate the SCF transcription under hypoxia. The results of colony formation, cell scratch, and transwell migration assay showed that SCF promoted the proliferation and invasion of PANC-1 cells under hypoxia. Furthermore, the down-regulated ability of cell proliferation and invasion following HIF-1α knockdown was rescued by adding exogenous SCF under hypoxia in vitro. Finally, when the HIF-1α expression was inhibited by digoxin, the tumor volume and the SCF level decreased, thereby proving the relationship between HIF-1α and SCF in vivo. In conclusion, SCF is an important factor for the growth of PDAC. In our experiments, we proved that SCF, a downstream gene of HIF-1α, can promote the development of PDAC under hypoxia. Thus, SCF might be a potential therapeutic target for PDAC.

In cancer cell lines inhibition of SCF/c-Kit pathway leads to radiosensitization only when SCF is strongly over-expressed

“…This activity was shown to have an oncogenic potential by driving tumor cell proliferation, migration and cancer stemness [7] , [8] , [9] , [10] , [11] , [12] . In line with this, for many tumors high level of SCF/c-Kit were found to be associated with poor prognosis [11] , [12] , [13] , [14] , [15] .…”

Stem cell factor in the serum of patients with esophageal cancer in relation to its histological types

“…It was found that several cell lines of malignant tumors are capable of secreting large amounts of HGFs and expressing their receptors [ 20 , 21 ]. Stem cell factor, also known as a steel factor, is a multifunctional cytokine that might be involved in tumor development [ 17 , 22 ]. Recently, increasing evidence has suggested that the SCF/c-kit system is up-regulated in several human malignancies and might play an important role in the angiogenesis, proliferation and invasion of tumor cells [ 17 , 23 ].…”

“…Stem cell factor, also known as a steel factor, is a multifunctional cytokine that might be involved in tumor development [ 17 , 22 ]. Recently, increasing evidence has suggested that the SCF/c-kit system is up-regulated in several human malignancies and might play an important role in the angiogenesis, proliferation and invasion of tumor cells [ 17 , 23 ]. Oka et al demonstrated the mRNA expression of SCF in human esophageal cancer cell lines [ 11 ].…”

Leptin signaling and cancer chemoresistance: Perspectives

“…TGF-β negatively regulates ALDH1 expression (a PCSC marker) in a SMAD dependent manner in PC cells. This regulatory mechanism might be disrupted by SMAD4 mutations and deletions in PC cells[131]. The binding of stem cell factor (SCF, a protein involved in PC progression) to its receptor, c-kit, determines an increase in HIF-1α synthesis that affects cancerous transformation, chemoradiotherapy resistance, and tumor progression[132].…”