PCa is the most frequently occurring cancer in men and advanced metastatic PCa is currently incurable. It is the great challenge of current basic and clinical research to identify novel molecular markers that could improve the tumor classification and prognostic stratification of PCa. The main findings of the present study are as following five points. Firstly, using gene microarray system, SOX7, SOX9 and SOX10 were identified as candidate genes which were differentially expressed in PCa compared with non-cancerous prostate tissues; Secondly, the de-regulation of SOX7, SOX9 and SOX10 genes and proteins in PCa tissues were further confirmed by real-time quantitative RT-PCR and immunohistochemistry analysis; Thirdly, the expression levels of SOX7, SOX9 and SOX10 in PCa tissues were related to the severity of the tumor malignancy; Fourthly, the down-regulation of SOX7 and the up-regulation of SOX9 were both independent predictors of shorter biochemical recurrence free-survival of patients with PCa; and finally, the down-regulation of SOX7 and the up-regulation of SOX9 at both gene and protein levels were observed during castration-resistant progression in xenograft tumor mouse models. These results suggest the SOX7, SOX9 and SOX10 play important roles in the pathogenesis and aggressiveness of PCa, and SOX7 and SOX9 especially be associated with the prognosis and be involved in the castration-resistant progression of PCa.
The main functions of the SOX gene family are as following [13–16]: Firstly, SOX genes regulate specification and differentiation of many cell types, such as neurogenesis, neural crest development, chondrogenesis, male sex gonad or respiratory epithelium development, melanocyte differentiation, and the differentiation of Paneth cells in the gut; Secondly, SOX genes within the same subgroup often share functional roles; Thirdly, SOX genes within the same subgroup can counteract the function of genes in another subgroup, and fourthly the same SOX gene can mediate different stages of development in one cell type and/or developmental processes in more than one cell type. Based on phylogenetic analysis of their HMG domains, SOX genes can be separated into subgroups A-J, A-H of which are represented in mouse and humans . Because they are expressed in many tissues, it is not surprisingly that SOX genes are implicated in the etiology of many diseases and certain cancers. In the present study, we identified three SOX genes (SOX7, SOX9 and SOX10) as the genes of interest, because they were differentially expressed in PCa compared with adjacent benign prostate tissues using the gene microarray system (Table 2). The down-regulation of SOX7 and SOX10, and the up-regulation SOX9 genes and proteins in PCa tissues were further confirmed by the real time quantitative RT-PCR and immunohistochemistry analysis, when compared to the corresponding non-cancerous prostate tissues.
SOX7 gene belongs to SOX subgroup F, which also includes SOX17 and SOX18 . It encodes a transcription factor that can both enhance and inhibit transcription. SOX7 is mainly implicated in parietal endoderm differentiation . According to the previous studies, SOX7 mRNA is undetected in some human cancer cell lines including HeLa S3 (cervical cancer), K562 (chronic myelogenous leukemia), SW480 (colorectal cancer), etc., suggesting that SOX7 might be a tumor suppressor gene in these cancers . In PCa, SOX7 mRNA and protein expressions were both shown to be down-regulated, which was consistent with the findings of this study and was found to be due to tumor-specific promoter hypermethylation present in PCa tissues and PCa cell lines/xenografts . Interestingly, we further demonstrated that the expression level of SOX7 protein in PCa tissues with higher serum PSA level and metastasis were significantly lower than those with lower serum PSA level and without metastasis. SOX9, together with SOX8 and SOX10, belongs to SOX subgroup E [21, 22]. It is a downstream effector of SRY, which in turn is dependent on the activity of androgens and the AR. There have been several studies on the involvement of SOX9 in PCa. In 2004, Drivdahl et al.  found that the elevated expression of SOX9 in PCa cell lines resulted in a decreased rate of cellular proliferation, cell cycle arrest in G0/G1, and increased sensitivity to apoptosis. In 2007 and 2008, Wang et al. [7, 8] also demonstrated that SOX9 was expressed in PCa cells and was increased in relapsed hormonerefractory PCa. In 2010, Thomsen et al.  identified SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it promotes tumor cell proliferation. All these previous studies were similar to the findings of our study. SOX10 has been implicated in the late stage of neural crest cell formation, maintenance of multipotency crest cells as stem cells and specification of derivative cell fates to Schwannian and melanocytic destinations [24–26]. Mutations in the SOX10 gene have been reported in a fraction of both primary and metastatic melanoma tumors . The immunohistochemistry analysis has also been employed to map the expression of SOX10 in various human tissues and SOX10 has been suggested to be a specific and sensitive marker for melanocytic tumors . However, the role of SOX10 in the development of PCa is not clear. From our investigation, SOX10 has been shown to be down-regulated and was associated with the high serum PSA levels and advanced pathological stage in PCa tissues.
An accurate prediction of the probability of disease recurrence is essential for proper therapy selection of PCa tissues. Thus, we investigated the prognostic significances of SOX7, SOX9 and SOX10 in the present study. Our results revealed that the expression of SOX7 and SOX9 in PCa correlated with biochemical recurrence-free survival. Patients with shorter follow-up time had tumors with a significantly lower expression of SOX7 and higher expression of SOX9, which indicated that tumors in patients with biochemical recurrence harbored SOX7 down-regulation and SOX9 up-regulation. In order to determine whether three SOX genes are involved in the progression to castration resistance PCa, we detected the changes of their expression in xenograft tumor mouse models. Our data showed the SOX7 down-regulation and the SOX9 up-regulation during the process of castration resistance, which suggested that the de-regulation of SOX7 and SOX9 may be one of the mechanisms responsible for the progression to castration resistance PCa. The exact roles of SOX7, SOX9 and SOX10 in the development of castration resistance are worth to be further investigation.