Abstract
The bottleneck arising from castration-resistant prostate cancer (CRPC) treatment is its high metastasis potential and antiandrogen drug resistance, which severely affects survival time of prostate cancer (PCa) patients. Secreted phosphoprotein 1 (SPP1) is a cardinal mediator of tumor-associated inflammation and facilitates metastasis. In our previous study, we firstly revealed SPP1 was a potential hub signature for predicting metastatic CRPC (mCRPC) development. Herein, we integrated multiple databases to explore the association of SPP1 expression with prognosis, survival, and metastatic levels in CRPC progression and investigated SPP1 expression in PCa tissues and cell lines. Next, PCa cell lines with overexpression or depletion of SPP1 were established to study the effect of SPP1 on enzalutamide sensitivity and adhesion and migration of prostate cancer cell lines and further explore the underlying regulatory mechanisms. Bioinformatics analysis, polymerase chain reaction (PCR), immunohistochemical staining, and western blot results suggested SPP1 upregulation had strong relationship with the malignant progression of CRPC and enzalutamide resistance. SPP1 knockdown enhanced enzalutamide sensitivity and repressed invasion and migration of prostate cancer cells. Importantly, upregulating SPP1 promoted, while silencing SPP1 attenuated epithelial-mesenchymal-transition (EMT). Our results further demonstrated that SPP1 overexpression maintains the activation of PI3K/AKT and ERK1/2 signaling pathways. Overall, our findings unraveled the functional role and clinical significance of SPP1 in PCa progression and help to discover new potential targets against mCRPC.
Highlights
Prostate cancer (PCa) is the most common malignancy, which causes the fifth rank of cancer-related mortality and is approximated 1,410,000 deaths and accounts for almost 14% of total cancer diagnosed in men [1, 2]
It was reported that Tumor mutational burden (TMB) in the lethal metastatic CRPC (mCRPC) clinical state, which was not controlled by androgen ablation, was significantly increased, and had a good relationship with PCa patients’ advancing clinical state and Gleason score [18]
In PCa, we found the expression level of Secreted phosphoprotein 1 (SPP1) mostly correlated with TMB level with P value as 1:4e − 06 (Figure 1(b))
Summary
Prostate cancer (PCa) is the most common malignancy, which causes the fifth rank of cancer-related mortality and is approximated 1,410,000 deaths and accounts for almost 14% of total cancer diagnosed in men [1, 2]. A significant feature of PCa is its hormone responsiveness, initially identified by Huggins and Hodges in 1941, who recognized that castration caused tumor regression in PCa patients [3]. Oxidative Medicine and Cellular Longevity long-term survival in localized PCa, antiandrogen treatment resistance can lead to primary castration-resistant prostate cancer (CRPC) or even metastatic CRPC (mCRPC) [4]. PCa is still a critical medical problem for the males affected, with excessive medical treatment of inherently benign disease and deficient effective treatment for metastatic PCa [5]. The underlying mechanisms of metastasis and antiandrogen treatment resistance of PCa are still not completely cleared
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