β-2-Microglobulin Is an Androgen-Regulated Secreted Protein Elevated in Serum of Patients with Advanced Prostate Cancer

Abstract

Purpose: A better understanding of secreted proteins may lead to the discovery of new biomarkers, which, along with prostate-specific antigen (PSA), may be useful in the diagnosis and treatment of prostate cancer patients. Experimental Design: Conditioned medium was collected from LNCaP cells following stimulation with methyltrienolone (R1881), 17h-estradiol (estradiol), or interleukin-6 and analyzed for differential protein expression with surface-enhanced laser desorption/ionization-time of flight mass spectrometry. Quantitative reverse transcription-PCR, immunoblots, and ELISA were used to measure h-2-microglobulin (B2M) message and protein levels in cells, conditioned medium, and serum. Results: Surface-enhanced laser desorption/ionization-time of flight revealed that many peaks were induced or repressed following stimulation with R1881or estradiol. A peak of interest centered at 11.8 kDa was chosen for additional analysis. Immunodepletion identified the peak of interest as B2M. Reverse transcription-PCR and immunoblots confirmed that PSA and B2M were induced by R1881. However, unlike PSA, B2M was not increased on stimulation with estradiol or interleukin-6. Human B2M is identified in the serum of mice bearing human prostate cancer xenograft. B2M is expressed in human prostate cancer cell lines and tissues. Serum B2M levels are elevated in patients with metastatic, androgen-independent prostate cancer. Conclusions: B2M is a secreted protein expressed in prostate cancer, which is more specific for androgen stimulation than PSA under the conditions tested. Additional studies are warranted to explore if B2M is as useful marker for prostate cancer. Identification of proteins secreted from cancer cells in preclinical models may be a useful strategy for biomarker discovery.Most serum biomarkers routinely used in the diagnosis and treatment of cancer are cell surface or secreted proteins expressed by both benign and malignant tissue. As these proteins are generally found at low abundance, highly sensitive tests (such as ELISAs) are required to measure biomarker levels in peripheral blood. However, the limited sensitivity and specificity of these tests often restricts their clinical utility. For example, prostate-specific antigen (PSA) is an androgenregulated secreted protein that is expressed by both normal and malignant prostate epithelial cells, which is widely used as a serum marker for prostate cancer (1). Occult prostate cancers may be found in f25% of patients with PSA levels in the generally accepted reference range (V4 ng/mL; ref. 2). Most, but not all, patients with metastatic prostate cancer show elevated levels of PSA, which is often used as a marker to guide treatment decisions. However, the validity of PSA as a surrogate to predict overall survival in advanced prostate cancer remains controversial (3,4). Therefore, additional biomarkers may be useful in the diagnosis and treatment of patients with prostate cancer.Serum-based protein profiling with mass spectrometry (MS) is a promising technolo...

Prognostic Values of Various Clinical Factors and Genetic Subtypes for Diffuse Large B-cell lymphoma Patients: A Retrospective Analysis of 227 Cases

“…β2-microglobulin (β2-M), a 11kDa non-glycosylated protein, exists in all nucleated cells (Cunningham et al, 1973;Güssow et al, 1987) and is involved in the regulation of the host immune response (Townsend et al, 1986;Pedersen et al, 1994), as well as a growth factor and signaling molecule in cancer cells. β2-M expression increases during progression of human prostate cancer (Gross et al, 2007), breast cancer (Teasdale et al, 1977), renal cancer (Hemmingsen and Skaarup, 1977), lung cancer (Shuster et al, 1976), colon cancer (Ward et al, 2008), and a number of liquid tumors (Yang et al, 2006).…”

Early biomarker discovery in urine of Walker 256 subcutaneous rat model

“…The expression trends of these corresponding proteins were consistent with the results from label-free quantification. [11], lung [12], colorectal [13], ovarian [14], rectal [15], gastric [16] Urine, blood, saliva, BALF P07151 P61769 Beta-2-microglobulin (B2MG) Yes Colon [17], Ovarian [18], prostate [19] Urine, blood…”

Test Article

“…Moreover, 2-m urine levels are higher in advanced prostate cancer patients with bone and visceral metastasis compared to those with local/regional disease [25]. Gross et al reported that serum 2-m levels are also elevated in patients with metastatic, androgen-independent prostate cancer, and 2-m is more specific for androgen stimulation than prostatespecific antigen (PSA) in a cell culture model [53]. PSA, the most widely used serum marker for prostate cancer diagnosis and evaluation of treatment, is an androgen-regulated secreted protein, but the validity of PSA for predicting tumor burden and survival remains controversial, partly because PSA originates from both normal, benign and malignant prostate epithelial cells.…”

“…Gross et al reported that 2-m is a downstream androgen target gene under the control of AR in a human prostate cancer cell line [53]. Interestingly, Huang et al showed a reciprocal relationship between 2-m and AR in which 2-m regulates downstream AR and PSA expression directly in AR-positive prostate cancer cells [69].…”