Serum and Saliva Concentrations of Biochemical Parameters in Men With Prostate Cancer and Benign Prostate Hyperplasia

Hyder Farahani, PhD; Mona Alaee, MSc; Jamal Amri, MSc; Mahmoud-Reza Baghinia, MD; Mohammad Rafiee, PhD

Disclosures

Lab Med. 2020;51(3):243-251. 

In This Article

Discussion

Evidence suggests that early detection is associated with reduced mortality from PC.[29] Therefore, it is necessary to find a potential marker for early diagnosis.[2] Our study results showed that serum and salivary concentrations of PSA, CK-BB, zinc, B2M, urea, and creatinine were increased in patients with PC, compared with patients having BPH. However, serum and salivary concentrations of MT were decreased in patients with PC compared with patients having BPH.

Although PSA is widely used in the detection of PC, there are some disadvantages to this method, such as low specificity and false-positive results.[8] In the results of the present study, serum and salivary PSA concentrations showed significant increases in PC, compared with BPH (P <.001); these findings are in agreement with those of other reports.[26,30,31] Also, PSA concentrations were lower in saliva, compared with serum, in both groups; these findings also agree with those from previous studies.[32,33] In addition, we discovered a positive significant correlation between serum and salivary concentrations of PSA in patients with PC (r = 0.61; P = .03) and those with BPH (r = 0.53; P = .04).

In a similar study, Shiiki et al[32] found a direct correlation between serum and salivary PSA concentrations in patients with high serum PSA concentration. However, this association was not observed in the group with low serum concentration of PSA. Another study, by Turan et al,[34] measured the free and total PSA in men with BPH, men with PC, and healthy controls. For all participants, there was significant correlation between free and total PSA concentrations in the serum and saliva specimens. There was also significant difference between the 3 groups for serum-free and total PSA concentrations. However, no significant difference was found in saliva PSA concentrations between groups.[34]

MT (or N-acetyl-5-methoxy-tryptamine) is the main product of the pineal gland in humans.[10] Recent study reports[35,36] have stated that treatment with MT has been associated with a significant reduction of cancer cells and with stopping the cell-cycle progression in LNCaP (lymph node carcinoma of the prostate) and PC3 cells. It has been reported[12] that melatonin limits glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway in PC cells. MT also inhibits Sirt1 protein function in human PC cells, which is associated with significant reduction in the proliferation of cancer cells.[13] Other potential mechanisms of MT in reduction of tumoral angiogenesis include inhibiting the expression of hypoxia-inducible factor 1-alpha (HIF1A) protein and thus inducing hypoxia in cancerous cells.[37] The results of further studies, such as that by Talib,[10] have shown that MT reduces the activity of the sphingosine kinase-1 (SPHK1), which is a HIF-1A regulator, in PC3 cells under hypoxic conditions.

Our study findings showed that the concentrations of MT in the serum (P = .009) and saliva (P = .04) of patients with PC were significantly lower than those in patients with BPH and that the serum concentrations of MT were higher than salivary concentrations in all participants. Similar results were observed in earlier studies.[38,39]

Also, we observed significant positive correlation between salivary and serum concentrations of MT in patients with PC (r = 0.81; P = .001) and those with BPH (r = 0.81; P = .002). In contrast, Chang and Lin[40] reported lower salivary MT concentrations in patients with newly diagnosed lung cancer, compared with healthy controls. Also, some articles on studies on healthy subjects[41,42] have reported a positive correlation between serum and salivary concentrations of MT, which is consistent with the results of our study. Due to the fact that patients with PC have lower concentrations of MT than patients with BPH, the idea that MT can be effective against disease severity can be justified.[38]

Urea and creatinine are good indicators of renal function and elevation; their concentrations in serum indicate impaired renal function.[43] In a prospective study, a higher rate of creatinine was associated with an increased risk of PC.[44] In the present study, serum urea (P = .01) and creatinine (P = .005) concentrations in patients with PC were significantly higher than in patients with BPH. These findings correlated with those of a study by Reshma et al.[26] However, Joshi and colleagues[28] found that urea and creatinine serum concentrations in patients with PC were increased, compared with those concentrations in healthy subjects; however, that increase was not statistically significant.

Our results showed that serum concentrations of urea and creatinine were higher than salivary concentrations in all participants. Also, salivary concentrations of urea (P = .01) and creatinine (P = .004) were significantly increased in patients with PC, compared with those with patients having BPH. Further, a positive correlation was observed between salivary and serum creatinine concentrations (r = 0.74, P = .01 in the PC group; r = 0.73, P = .02 in the BPH group). There was a similar correlation between salivary and serum urea concentrations in patients with PC (r = 0.86; P = .001) and the BPH group (r = 0.73; P = .02).

B2M is a soluble protein that is secreted by cancer cells and host inflammatory cells.[45] Researchers[15] have observed increased urinary B2M in patients with advanced prostate cancer, accompanied with reduction in overall survival, among patients with bone metastases. In the results of another study,[46] excess B2M expression in malignant and borderline ovarian tumors, compared with benign ovarian tumors and healthy cells, was observed. This increase may be related to the invasive nature of the disease. Our results showed that serum and salivary B2M concentrations in patients with PC were significantly higher than those in patients with BPH (P = .02). Also, the B2M serum concentration in both groups was higher than the salivary concentration, and there was a significant positive correlation between serum and salivary concentrations in patients with cancer (r = 0.74; P = .02) and in the BPH group (r = 0.61; P = .04). Our results are in agreement with those of a previous study,[47] which showed that B2M serum concentration increased in patients with PC. Patients with metastases also showed a higher level of B2M compared to patients without metastases. Further, successful treatment of patients caused a decreased in B2M level, and an increase in B2M level was observed in cases of recurrence.[48]

To our knowledge, this is the first study in which salivary B2M concentrations and correlation between serum and salivary concentrations of B2M were determined in men with PC. However, in studies performed on patients with renal diseases, there was a correlation between serum and salivary concentrations of urea and creatinine but no correlation between serum and salivary B2M concentrations.[28,49,50]

CK plays a key role in the energy metabolism of vertebrate cells. In a study on ovarian cancer,[21] it was observed that creatine kinase B (CKB) knockdown inhibited cell proliferation in the ovarian-cancer cell line Skov3 and leads to apoptosis in hypoxic or hypoglycemic conditions. Further, knockdown of CKB induced G2 arrest in the cell cycle by increasing the expression of P21. Our study results showed that the serum (P = .03) and saliva (P = .01) concentrations of CKB in patients with PC were significantly higher than those levels in patients with BPH. In general, the serum CK-BB concentrations in both groups were higher than the salivary concentrations.

Consistent with our results, those of previous studies[51,52] introduced CK-BB as a suitable tumor marker for diagnosis of PC. Also, although Feld and colleagues[53] reported an increase in CK-BB concentration in people with prostate cancer and BPH, they concluded that CK-BB cannot be a suitable marker for early diagnosis. The results of a revious study[17] have shown that CK concentrations were significantly lower in patients with lung and breast cancer, compared with healthy subjects, and had a negative correlation with tumor size and grade. Our results also showed a positive significant correlation between serum and salivary CK-BB concentrations (r = 0.73, P = .02 in patients with PC; r = 0.72; P = .02 in the BPH group). To our knowledge, the present study is the first to evaluate the amount of salivary CK-BB in patients with PC.

Zinc is a vital nutrient for human health.[54] High concentrations of zinc in the prostate indicate that zinc plays an important role in prostate health, specifically.[55] Our study findings showed that zinc concentrations in the serum and saliva of patients with PC were significantly higher than those with BPH (P = .01). However, contrary to our results, Christudoss et al[56] reported that zinc plasma concentrations in patients with PC showed a 27% decrease compared with controls, and an 18% decrease compared with patients with BPH. Also, the results of another study[57] showed that zinc concentrations in patients with PC were significantly lower versus those in controls, and no significant changes between the PC and BPH groups was observed. Similarly, Kaba et al[58] reported that serum zinc concentration in patients with PC was decreased, compared with those levels in healthy controls. We discovered that the results of 2 separate studies[22,59] showed that serum zinc levels in patients with PC was higher than those in healthy subjects; this result is consistent with the findings that accumulation of zinc in prostate tissue can be a major cause of the onset and progression of PC. Also in our study, there was a positive significant correlation between serum and salivary concentrations of zinc in patients with PC (r = 0.76; P = .02) and in the BPH group (r = 0.79; P = 0.02). To our knowledge, there is no study in the literature on salivary concentration of zinc in people with prostate disease.

Sensitivity and specificity are the basic methods to determine the accuracy of a diagnostic test. To our knowledge, no studies to evaluate the sensitivity and specificity of saliva PSA, B2M, CK-BB, MT, zinc, creatinine, and urea hve been conducted for diagnosing prostate diseases. However, this study used ROC analysis to ascertain the diagnostic potential of a tool (saliva) as an alternative to a standard method (serum). The results of ROC analysis of salivary PSA, B2M, CK-BB, MT, zinc, creatinine, and urea, in our study, showed good accuracy with good sensitivity and specificity. These results further confirm the use of saliva instead of blood serum.

In conclusion, we observed that salivary diagnosis is a simple, noninvasive, and reliable technique to measure biological parameters. Furthere, there was an association between serum and salivary biochemical parameters and PC. Increased concentration of PSA, urea, creatinine, B2M, CK-BB, and zinc, and decreased MT concentration in serum and saliva can play important roles in the induction of PC. However, further studies are needed to confirm the relationship between serum and salivary concentrations of these parameters and PC. Examining other biomarkers in saliva and in various diseases with large sample sizes can help confirm the role of saliva as an appropriate laboratory specimen.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....