Prostate cancer is a serious illness that continues to present several different challenges to the urologists, pathologists, radiologists and oncologists . In recent times, the incidence rate of prostate cancer has been steadily increasing in China. Prostate cancer is the most common non-dermatologic cancer. Despite the high incidence rate of prostate cancer, its clinical course of treatment is often unpredictable [12, 13]. While treating prostate cancer at an advanced stage, patients are subjected to surgical or pharmacological castration. This is the most widely accepted method of treating prostate cancer at an advanced stage. However, the prostate tumor becomes hormone refractory after a period of 14 to 36 months. As the prostate tumor undergoes a transition from the hormone refractory stage to metastatic stage, it poses severe problems in clinical management . Gleason score , PSA [16, 17], clinical stage, and prostate volume are crucial parameters that need to be considered in the treatment of prostate cancer. Gleason score is an important prognostic factor for predicting biochemical failure, systemic recurrence, and overall patient survival . However, there may be variations in comprehending the Gleason score among pathologists . Note that, elevated levels of PSA can also be associated with BPH and prostatitis . Therefore, these biomarkers seem inadequate to precisely determine the possibility of recurrence or metastasis. Therefore, the underlying molecular mechanisms of prostate carcinogenesis should be further investigated and elucidated. These efforts will help us in finding a reliable biomarker that can help us in improving the evaluation and prognosis of patients with CRPC .
In this study, GOLPH3 expression was detected in most benign and malignant tissues. It is interesting to note that 98 (40.66%) of 241 prostate cancer showed GOLPH3 moderate/intense expression. This result confirmed the findings of previous studies that reported an over expression of GOLPH3 in 37% of prostate cancer cases .
Progression to androgen-independence is a complex process involving various combinations of clonal selection , adaptive up-regulation of anti-apoptotic genes [23–25], androgen receptor transactivation in the absence of androgen or increased levels of coactivators [26, 27], and alternative growth factor pathways [27, 28]. According to this study, no statistically significant difference was found in GOLPH3 expression of normal prostate tissue, BPH, and HDPC. In contrast, there was a statistical difference in GOLPH3 expression of CRPC and HDPC cases (p<0.0005). These findings suggested that the oncogene GOLPH3 was highly conserved throughout evolution. In fact, GOLPH3 was strictly regulated in normal tissues, since it was essential for normal cell growth. Furthermore, these data suggest the possibility of associating the over-expression of GOLPH3 with the progression of prostate cancer. This probability is more pronounced in the transition from hormone-sensitive to hormone-refractory tumors. But, we cannot decipher the correlation of GOLPH3 expression with cellular hyperproliferation and tumorigenesis, especially during the early stages of prostate cancer development.
mTOR is a serine/threonine protein kinase, which is found in both rapamycin-sensitive and rapamycin-insensitive multimeric protein complexes. To regulate cell growth, cell-cycle progression, and cell differentiation, mTOR functions as a central signal integrator that receives signals from growth factors, nutrients, and cellular energy metabolism [29, 30]. Therefore, mTOR is recognized as a central coordinator of these fundamental biological processes [31–33]. Note that, mTOR is an evolutionarily conserved protein kinase. Recent studies have reproted that GOLPH3 works as an oncoprotein promoting cell transformation and tumor growth by enhancing the activity of mTOR . Since mTOR is required for cell differentiation, hyperactivation of mTOR may be associated with abnormal cell differentiation. In conclusion, an overexpression of GOLPH3 causes an abnormal differentiation of prostate cancer cells, thereby creating heterogeneity of tumor cells. New subclones with altered growth properties proliferate owing to this trait of heterogeneity. In fact, the transition from hormone-sensitive to hormone-refractory tumors can be probably attributed to this molecular mechanism.
In this research study, it was found that the incidence of Gleason score, PSA nadir, baseline PSA, and positive bone metastasis was higher in patients detected with moderate/intense GOLPH3 expression. In our study, we also demonstrated that GOLPH3 over-expression was significantly associated with a shorter DFS and OS. Multivariate analysis revealed a significant negative relationship between the over expression of GOLPH3 and DFS or OS. Therefore, we can conclude that GOLPH3 serves as a biomarker for predicting the severity of prostate cancer. GOLPH3 expression is an important parameter used in the prognosis of prostate cancer patients.
In this research study, we have discovered that GOLPH3 expression does not have any correlation with cellular hyperproliferation and tumorigenesis, particularly in the early stages of prostate cancer. On the other hand, over-expression of GOLPH3 could be correlated with the progression of prostate cancer from its hormone sensitive phase to hormone refractory phase. Furthermore, GOLPH3 might be a favorable prognostic factor of DFS and OS in patients diagnosed with prostate cancer. In this way, GOLPH3 expression serves as a reliable prognostic marker. In fact, determining the expression of GOLPH3 might also help in further elucidating the risk of progression of prostate cancer in patients. In conclusion, GOLPH3 can be a novel candidate for the development of an effective therapeutic strategy for CRPC.