Chevrier Martin, Bobbala Diwakar, Villalobos-Hernandez Alberto, Khan Md Gulam Musawwir, Ramanathan Sheela, Saucier Caroline, Ferbeyre Gerardo, Geha Sameh, Ilangumaran Subburaj
Department of Pathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada.
Department of Pediatrics, Immunology division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada.
BMC Cancer. 2017 Feb 24;17(1):157. doi: 10.1186/s12885-017-3141-8.
Suppressor of cytokine signaling 1 (SOCS1) is considered a tumor suppressor due to frequent epigenetic and micro-RNA-mediated repression of its gene expression in diverse cancers. In prostate cancer (PCa), elevated expression of miR-30d that targets SOCS1 mRNA is associated with increased risk of disease recurrence. SOCS1 can mediate its tumor suppressor functions by diverse mechanisms such as inhibiting the JAK-STAT signaling pathway, promoting the tumor suppressor functions of p53, attenuating MET receptor tyrosine kinase signaling and blocking the oncogenic potential of the cell cycle inhibitor p21 (p21). Here, we studied the expression of SOCS1 and the downstream targets of its putative tumor suppressor functions (p53, MET and p21) in human PCa specimens to evaluate their significance as markers of disease prognosis.
Tissue microarrays were constructed of 78 archived prostatectomy specimens that were grouped according to the recommendations of the International Society of Urological Pathology (ISUP) based on the Gleason patterns. SOCS1, p53, MET and p21 protein expression were evaluated by immunohistochemical staining alongside the common prostate cancer-related markers Ki67, prostein and androgen receptor. Statistical correlations between the staining intensities of these markers and ISUP grade groups, local invasion or lymph node metastasis were evaluated.
SOCS1 showed diffuse staining in the prostatic epithelium. SOCS1 staining intensity correlated inversely with the ISUP grade groups (ρ = -0.4687, p <0.0001) and Ki67 (ρ = -0.2444, p = 0.031), and positively with prostein (ρ = 0.3511, p = 0.0016). Changes in SOCS1 levels did not significantly associate with those of p53, MET or p21. However, p21 positively correlated with androgen receptor expression (ρ = -0.1388, p = 0.0003). A subset of patients with regional lymph node metastasis, although small in number, showed reduced SOCS1 expression and increased expression of MET and p21.
Our findings suggest that evaluating SOCS1 and p21 protein expression in prostatectomy specimens may have a prognostic value in identifying the aggressive disease. Hence, prospective studies with larger numbers of metastatic PCa specimens incorporating clinical correlates such as disease-free and overall survival are warranted.
细胞因子信号转导抑制因子1（SOCS1）被认为是一种肿瘤抑制因子，因为在多种癌症中其基因表达经常受到表观遗传和微小RNA介导的抑制。在前列腺癌（PCa）中，靶向SOCS1 mRNA的miR-30d表达升高与疾病复发风险增加相关。SOCS1可通过多种机制介导其肿瘤抑制功能，如抑制JAK-STAT信号通路、促进p53的肿瘤抑制功能、减弱MET受体酪氨酸激酶信号传导以及阻断细胞周期抑制剂p21（p21）的致癌潜能。在此，我们研究了人PCa标本中SOCS1及其假定的肿瘤抑制功能的下游靶点（p53、MET和p21）的表达，以评估它们作为疾病预后标志物的意义。
用78份存档的前列腺切除标本构建组织微阵列，这些标本根据国际泌尿病理学会（ISUP）的建议基于Gleason模式进行分组。通过免疫组织化学染色评估SOCS1、p53、MET和p21蛋白表达，同时评估常见的前列腺癌相关标志物Ki67、前列腺素和雄激素受体。评估这些标志物的染色强度与ISUP分级组、局部浸润或淋巴结转移之间的统计相关性。
SOCS1在前列腺上皮中呈弥漫性染色。SOCS1染色强度与ISUP分级组呈负相关（ρ = -0.4687，p <0.0001），与Ki67呈负相关（ρ = -0.2444，p = 0.031），与前列腺素呈正相关（ρ = 0.3511，p = 0.0016）。SOCS1水平的变化与p53、MET或p21的水平无显著相关性。然而，p21与雄激素受体表达呈正相关（ρ = -0.1388，p = 0.0003）。一部分区域淋巴结转移患者，尽管数量较少，但显示出SOCS1表达降低以及MET和p21表达增加。
我们的研究结果表明，评估前列腺切除标本中SOCS1和p21蛋白表达可能对识别侵袭性疾病具有预后价值。因此，有必要对更多转移性PCa标本进行前瞻性研究，并纳入无病生存期和总生存期等临床相关指标。
