| Background:Prostate cancer(PCa)is the most common malignancy in male urogenital system.Although its incidence in China is lower than the average level of Europe and the United States,it is rising every year.Endocrine therapy is currently the main treatment method for PCa and its treatment effect is remarkable in the early stage of disease.Nevertheless almost all patients will inevitably progress into castration resistant prostate cancer(CRPC)after a period of treatment.At present,the pathogenesis of CRPC remains unclear,and no effective treatment has been invented.Abnormal activation of androgen receptor(AR)signaling pathways plays an important role in the occurrence and development of CRPC.STIL gene,as a proto-oncogene,has proved to be abnormally activated in PCa tissues and could inhibit tumor cell apoptosis.STIL gene may upregulate AR receptor expression and reactivation of androgen receptors.Objective1.To identify the overexpression of STIL gene in Chinese patients with CRPC.2.To discover the molecular role of STIL gene in the occurrence and development of CRPC.3.To provide potential targets for CRPC.Method:The chip data in GEO were downloaded,processed,and then analyzed using R language programs to compare the expression level of STIL gene between hormone sensitive prostate cancer(HsPCa)and CRPC.Transcriptomic data of PCa and paracancerous tissues were extracted and downloaded from the Cancer Genome Atlas(TCGA).Differential analysis was conducted to explore the expression level of STIL in PCa.Receiver operating characteristic(ROC)curve of STIL in PCa was also plotted.We used String dataset to analyze the interaction between STIL,AR,and proteins from SHh/Hippo signal pathway,and draw a protein interaction diagram.To further validate the abovementioned findings,we obtained surgical samples from 10 cases of CRPC,10 cases of HsPCa,and 20 cases of benign prostatic hyperplasia(BPH)patients treated in our center.We compared the expression level of STIL gene among these patients through immunohistochemistry and quantitative polymerase chain reaction(qPCR).We used shRNA plasmid to knock down the expression of STIL gene in 22Rv1 and MDA-PCa-2b cell lines,and used qPCR to detect the expression level of SHh/Hippo signaling pathway and AR receptor.Results:According to the data from GEO database,the STIL expression level in CRPC group was significantly higher than that in HsPCa group(P=0.02).TCGA database analysis showed that STIL gene expression level in patients with score 8,9,and 10 were significantly higher than patients with score 6 and 7(p=0.008).In addition,the expression level of STIL gene in PCa patients with prostate specific antigen(PSA)concentration≤4ng/ml was significantly lower than patients with PSA concentration>4ng/ml(p=0.04),and the expression of STIL gene in patients with pathological stage T2 was significantly lower than patients with T3 and T4(T3:P=0.04,T4:P=0.03).The expression level of STIL gene in patients with lymph node metastasis was significantly higher than patients without lymph node metastasis(p=0.03).Studies have shown that the expression level of STIL gene is closely related to the TNM stage of cancer.Gene co-expression analysis showed that the STIL gene expression level in Sonic Hedgehog(SHh)signal pathway was correlated with SUFU and GLI1,whereas STIL in the Hippo signal pathway was correlated with YAP and LATS1.The expression level of STIL gene was positively correlated with AR.Immunohistochemical results showed that the STIL positive rate of CRPC tissue was significantly higher than HsPCa and BPH tissue.The results of qPCR suggested that STIL mRNA expression leve in CRPC tissue was significantly higher than BPH and HsPCa tissue(P<0.05).Conclusion:STIL gene is highly expressed in CRPC,and could regulate the occurrence and development of CRPC through SHh/Hippo signaling pathway.In addition,STIL gene is associated with malignancy of PCa,TNM stage,and has the potential to become a therapeutic target for CRPC. |
