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ARHGEF38 as a novel biomarker 7
cancers except breast cancer in the United States. In addition, the analysis of RNA-seq PRAD data from the TCGA dataset indicated that ARHGEF38 is significantly upregu-lated in PCa compared to normal prostate tissue and the ARHGEF38 Calpain Inhibitor I positively correlated with the degree of cancer progression.
ARHGEF38 expression levels were confirmed using the PCa samples from patients. We observed that ARHGEF38 was increased in the PCa tissues both at the mRNA and protein levels. The results from the present study demon-strated that ARHGEF38 is significantly overexpressed in PCa than BPH, especially, high-grade prostate cancer. This suggested that ARHGEF38 might promote prostate cancer migration and hence attribute to PCa progression. We also analyzed the association between ARHGEF38 expression and clinicopathological features in PCa patients. The re-sults suggested that the ARHGEF38 expression was posi-tively correlated with GS and the pathology stage. Solid tumor progression is characterized by metastasis to regional lymph nodes and dissemination to distant organs. Lymph node metastases in cancer patients are associated with tumor aggressiveness and poorer prognoses.25e27 ARHGEF38 protein in lymph node metastasis patients was significantly higher than that in the non-metastatic pa-tients, which may suggest that the high expression of ARHGEF38 is more prone to distant metastasis; thus, ARH-GEF38 could be an indicator for PCa metastasis. Thera-peutic strategies and diagnosis for stage-specific PCa have not been well understood. In this study, ARHGEF38 and Ki67 can clearly distinguish T1, T2 and T3 from PCa, providing useful support for further treatment strategies. Ki67 is a well-known proliferation marker used in pathological grading. It has been reported to predict the clinical outcome in prostate cancer.28,29 Our results showed that the expression of the Ki67 protein was high in HGPCa similar to the previous report by Lynn et al.30 We also demon-strated a positive correlation between Ki67 and ARHGEF38.
The Kaplan Meier Survival analysis showed lower survival rates with an increased expression of ARHGEF38 and Ki67. The probability of 5-year tumor-free survival of patients with low ARHGEF38 expression was 5.3 times (TCGA) and 6.5 times (follow-up patients) higher than the patients with high ARHGEF38 expression. Similarly, the probability of 5-year tumor-free survival of patients with low Ki67 expres-sion was 2.09 times higher than the patients with high Ki67 expression. Collectively, the present study hints a novel biomarker to detect PCa prognosis, which might help to design better treatment strategies for better survival rates of PCa patients.
The present study unravels the differentially expressed genes in PRAD from GEO datasets, which were further verified using TCGA data. The functional enrichment anal-ysis indicated that most of the DEGs were related to metastasis. Through IHC and qRT-PCR analyses, we found that expression of ARHGEF38 in high-grade prostate cancer was higher than that in low-grade prostate cancer, espe-cially in GS8 patients, and the expression was higher than that in GS7 and GS2-6 patients. The expression of
ARHGEF38 in patients with lymph node metastasis was higher than in the non-lymph node metastasis patients. We also found a positive correlation between Ki67 and ARH-GEF38 in prostate cancer. The higher expression of both worsened the prognosis. Taken together, our results reveal that ARHGEF38 might play a crucial role in tumorigenesis and metastasis of human PCa and might function as a po-tential prognostic indicator of PCa. This might further shed light on to the development of therapeutic strategies ac-cording to the aggressiveness of PCa by allowing early diagnosis and prognosis of PCa.
Conflict of interest
The authors have no conflict of interest.
The study was funded by the Tianjin Medical University Second Hospital Fund (2017ydey06) and Chongqing Science and Technology Commission (cstc2018jcyjAX0199). We are very grateful to the participants and staff in the Center for Molecular Diseases and Cancer Research of Chongqing Medical University. In addition, we also thank the Institute of Urology of Tianjin Medical University for the paraffin section.
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5. Seibert TM, Fan CC, Wang Y, et al. Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts. BMJ. 2018;360:j5757.
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