JAK/STAT信号通路在卵巢高级别浆液性癌中的激活及预后意义

doi:10.19723/j.issn.1671-167X.2023.02.010

摘要/Abstract

摘要：

目的: Janus激酶(Janus kinase, JAK)、信号转导和转录活化因子(signal transducers and activators of transcription, STAT)构成的JAK/STAT信号通路的活化与卵巢高级别浆液性癌(high-grade serous carcinoma, HGSC)的预后和靶向治疗密切相关。本研究力求通过简单易行的检测手段, 评估JAK/STAT信号通路的活化在卵巢HGSC中的预后意义。方法: 运用免疫组织化学染色方法, 对73例卵巢HGSC的病理切片进行磷酸化STAT3(pSTAT3)和磷酸化STAT5(pSTAT5)染色, 并对二者的染色强度及染色范围进行定量评估。以此为标准, 将HGSC病例分为pSTAT3低/高表达组以及pSTAT5低/高表达组, 并对不同分组的患者预后情况进行分析, 探究pSTAT3和pSTAT5的表达与HGSC预后的关系。结果: 部分卵巢HGSC存在pSTAT3和pSTAT5蛋白的高表达, 且二者的表达与HGSC的预后相关。pSTAT3和pSTAT5蛋白的表达水平在预后较好组(生存期≥3年)和预后较差组(生存期 < 3年)中的差异有统计学意义, 伴有pSTAT3高表达、或pSTAT5高表达、或pSTAT3和pSTAT5皆高表达的HGSC病例预后更差, 表现为疾病无进展生存期以及总生存期均显著低于对应的低表达组(P < 0.001)。结论: 通过pSTAT3、pSTAT5蛋白的免疫组织化学染色, 可以实现对卵巢HGSC患者进行风险评估, 可协助判断预后同时筛选高危人群, 为STAT抑制剂及抗血管生成药物的适用人群提供有益的参考指标。

关键词: 信号转导和转录激活因子, Janus激酶类, 卵巢肿瘤, 高级别浆液性癌

Abstract:

Objective: The activation of Janus kinase (JAK) and signal transducers and activators of transcription (STAT) plays an important role in the prognosis and targeted therapy of ovarian high-grade serous carcinoma (HGSC). Utilizing simple and practicable technique, this study aimed to evaluate the activation of JAK/STAT signaling pathway in ovarian HGSC patients, and investigated the correlation between the activation of JAK/STAT signaling pathway and the prognosis of the HGSC patients. Methods: We performed immunohistochemistry of phosphorylated STAT3 (pSTAT3) and phosphorylated STAT5 (pSTAT5) on paraffin imbedded slides of 73 ovarian HGSC patients, and evaluated the expression level and range of both markers. According to the grading score of the immunostaining of pSTAT3 and pSTAT5, we divided the 73 ovarian HGSC cases into STAT3 low/high expression and STAT5 low/high expression groups, and analyzed the prognosis of the patients in different groups, in order to explore the relationship between the expression of pSTAT3 and pSTAT5 proteins and the prognosis of the HGSC patients. Results: Some of the ovarian HGSC cases showed high expression of pSTAT3 and pSTAT5 protein level, which was related to the poorer prognosis of the HGSC patients. There was a significant difference in the expression level of pSTAT3 and pSTAT5 between the patients with better prognosis (survival time ≥3 years) and poorer prognosis (survival time < 3 years). The patients with higher protein expression of pSTAT3, pSTAT5 or both markers might have poorer prognosis, with significant shorter progression-free survival time and overall survival time (P < 0.001). Conclusion: Immunostaining of pSTAT3 and pSTAT5 proteins might be helpful to evaluate and predict the prognosis of the ovarian HGSC patients, and to identify the patients who might have higher chances to respond to the STAT inhibitors and anti-angiogenesis therapy.

Key words: Signal transducer and activator of transcription, Janus kinases, Ovarian neoplasms, High-grade serous carcinoma

中图分类号:

R737.31

杨菁,杜娟,王玉湘,刘从容. JAK/STAT信号通路在卵巢高级别浆液性癌中的激活及预后意义[J]. 北京大学学报（医学版）, 2023, 55(2): 270-275.

Jing YANG,Juan DU,Yu-xiang WANG,Cong-rong LIU. Activation of JAK/STAT in ovarian high-grade serous cancers and its prognostic significance[J]. Journal of Peking University (Health Sciences), 2023, 55(2): 270-275.

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参考文献 10

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Positive cells		Staining intensity		Result evaluation
Percentage	Score	Intensity	Score	Group	Final score^*
< 10%	1	No staining	0	pSTAT3-low	0-4
10%-80%	2	Yellow	1	pSTAT3-high	5-9
>80%	3	Yellowish brown	2	pSTAT5-low	0-4
		Brown	3	pSTAT5-high	5-9

Parameters	Counts (n=73)	pSTAT3			pSTAT5			pSTAT3+pSTAT5
Parameters	Counts (n=73)	Low expression (n=49)	High expression (n=24)	P value	Low expression (n=48)	High expression (n=25)	P value	Low expression (n=53)	High expression (n=20)	P value
Age/years				0.13			0.52			0.19
< 50	27 (37.0)	21 (77.8)	6 (22.2)		19 (70.4)	8 (29.6)		22 (81.5)	5 (18.5)
≥50	46 (63.0)	28 (60.1)	18 (39.9)		29 (59.2)	17 (40.8)		31 (67.4)	15 (32.6)
FIGO stage				0.15			0.42			0.24
Ⅰ	9 (12.3)	4	5		5	4		6	3
Ⅱ	14 (19.2)	10	4		9	5		11	3
Ⅲ	38 (52.1)	29	9		28	10		30	8
Ⅳ	12 (16.4)	6	6		6	6		6	6
PFS				< 0.01			< 0.001			< 0.001
< 3 years	36 (49.3)	15 (20.5)	21 (28.8)		13 (17.8)	23 (31.5)		17 (23.3)	19 (26.0)
≥3 years	37 (50.7)	34 (46.6)	3 (4.1)		35 (48.0)	2 (2.7)		36 (49.3)	1 (1.4)
OS				< 0.001			< 0.001			< 0.001
< 3 years	30 (41.1)	10 (13.7)	20 (27.4)		8 (11.0)	22 (30.1)		12 (16.4)	18 (24.7)
≥3 years	43 (58.9)	39 (53.4)	4 (5.5)		40 (54.8)	3 (4.1)		41 (56.2)	2 (2.7)