Overexpression Of Solute Carrier Family 6 Member 1(SLC6A1)Promotes Prostate Cancer Progression And Its Resistance To Chemotherapy

Background and purpose:Prostate cancer(PCa)is the most common malignancy in men,and its morbidity and mortality in China are increasing year by year.The current treatments include androgen deprivation therapy(ADT),surgery,immunotherapy,chemotherapy and so on.However,despite the effective treatment,including castration,radical prostatectomy and high-dose radiotherapy,20-30%of prostate cancer patients have biochemical relapse within 5-10 years and progress to castrated resistant prostate cancer(CRPC).Docetaxel is a first-line drug approved by FDA for the treatment of CRPC.However,more than half of CRPC patients are resistant to docetaxel.Therefore,searching for a method to predict the efficacy of docetaxel will be helpful for the treatment of CRPC.Previous studies have shown that solid carrier family 6 member 1(SLC6A1)acts as a cancer promoting factor,promoting the resistance of some tumors to chemotherapy.However,the expression of SLC6A1 in prostate cancer and its effect on docetaxel chemotherapy have not been reported.Based on this,for the first time,this study will explore the correlation between SLC6A1 and the progression and prognosis of prostate cancer,clarify the expression of SLC6A1 in prostate cancer,and explore the influence of SLC6A1 expression on chemotherapy resistance of prostate cancer and its possible mechanism.Method:1.The relationship between the expression of SLC6A1 and the pathological properties of prostate was analyzed by immunohistochemistry in clinical gene chip.The correlation between the expression of SLC6A1 in TCGA database and the clinical characteristics of prostate cancer patients was analyzed.The relationship between SLC6A1 expression and non-metastasis biochemical recurrence of prostate cancer was studied by using survival curve.The Cox regression model was used to analyze whether SLC6A1 could be a predictor of prostate cancer prognosis.2.To construct cell lines with overexpression or lowexpression of SLC6A1,and to verify the effect of SLC6A1 on the proliferation,metastasis and invasion,cell cycle of prostate cancer cells.3.The ROS changes of cell lines overexpressing or inhibiting expression of SLC6A1 were detected,and the activity of cells and the changes of ROS were observed after docetaxel treatment.4.SLC6A1 overexpression or inhibition of PC3 cell line were inoculated into nude mice skin to observe the effect of SLC6A1 on prostate cancer in vitro.After tumorigenesis,docetaxel was used to treat.5.The transplanted tumor tissues were analyzed by immunohistochemistry,and the difference of MMP-9 and PCNA expression was analyzed.Result:1.The expression of SLC6A1 was significantly correlated with the pathological properties of prostate tissue(P=0.004),and it was highly expressed in prostate cancer.TCGA database analysis showed that SLC6A1 was correlated with Gleason score,clinical stage and non-metastasis biochemical recurrence of prostate cancer(P<0.001,<0.001,0.042).2.In TCGA database and Taylor database,SLC6A1 is a cancer promoting gene,and high expression of SLC6A1 indicates poor prognosis of prostate cancer patients(P=0.002,P=0.026).Single factor and multi factor analysis of Cox regression model showed that SLC6A1 may be used as a predictor for the survival of prostate cancer patients with nonbiochemical recurrence.3.The results of cell function experiment showed that overexpression of SLC6A1 could promote the proliferation,metastasis and invasion of prostate cancer cells,and promote cell cycle(P<0.05),while lowexpression of SLC6A1 could inhibit the proliferation,metastasis and invasion of prostate cancer cells,and inhibite cell cycle(P<0.05).4.ROS decreased largely in the SLC6A1 overexpression of PC3 and LNCaP cell lines,and increased obviously in the SLC6A1 low-expression group.The concentration of docetaxel IC50 was 33.89nm in PC3 cells and 3.40nm in LNCaP cells.After treatment with docetaxel,the activity of cells in SLC6A1 overexpression group increased,apoptosis decreased and ROS decreased,while the activity of cells in SLC6A1 inhibition group decreased,apoptosis increased and ROS increased.5.SLC6A1 can promote the growth of transplanted tumor in vitro.Docetaxel can inhibit the growth of transplanted tumor in nude mice,but the tumor with overexpression of SLC6A1 does not shrink after treatment.6.The expression of MMP-9 and PCNA decreased in the transplanted tumor with lowexpression of SLC6A1(P<0.05).Conclusion:1.As a cancer promoting factor,SLC6A1 can promote the occurrence and development of prostate cancer in vitro and in vivo,and may be a predictor of biochemical recurrence free survival of prostate cancer patients.2.Overexpression of SLC6A1 promotes chemoresistance to prostate cancer.3.The change of ROS may be the potential mechanism of chemotherapy resistance in prostate cancer.