卵巢癌由于诊断晚和缺乏有效的有针对性治疗而成为妇科癌症中死亡率最高的一种。虽然癌细胞和其微环境之间相互作用的研究正在兴起，但卵巢癌如何触发信号与免疫细胞协同以促进转移仍然不为人们所知。本研究使用低侵袭性和高侵袭性卵巢癌细胞的微阵列和生物信息学分析揭示了多功能的基质蛋白periostin（POSTN）在高侵袭性细胞中表达升高。我们进行了无定形基质独立实验、蛋白质印迹、RNA干扰、共聚焦分析和中和抗体处理，以分析POSTN对肿瘤促进的影响和探索其潜在机制。我们进行了趋化性、流式细胞术和细胞因子阵列分析以分析POSTN在癌相关成纤维细胞（CAF）和巨噬细胞调控中的参与情况。我们使用Oncomine，商业卵巢癌cDNA和中国医科大学医院患者队列分析POSTN表达水平与临床特征之间的相关性。我们使用小鼠异种移植模型研究了POSTN对转移的影响。发现高侵袭性卵巢癌细胞中POSTN的表达升高。POSTN与整合素β3和整合素β5共定位重要，这对POSTN介导的ERK和NF-κB的活化至关重要。POSTN的外源表达增强了癌细胞的迁移和入侵（体外），同时降低了肿瘤的生长和转移（体内）。POSTN通过一种自分泌作用作用于癌细胞，激发肿瘤吸引和动员细胞因子，包括MIP-1β，MCP-1，TNFα和RANTES，从而增加了THP-1单核细胞的趋化性并导致它们向M2型巨噬细胞的极化（体外）。POSTN能够诱导卵巢癌细胞表达TGF-β2，以促进脂肪来源的基质细胞激活成α平滑肌肌动蛋白和成纤维细胞激活蛋白α表达的CAF样细胞。一致地，从POSTN过度表达的SKOV3衍生的转移性肿瘤中观察到了增加的CAF。在临床相关性方面，我们发现POSTN的表达与晚期疾病和患者总生存率不良呈正相关。本研究揭示了POSTN-整合素-NF-κB介导的信号传导及其参与增强M2型巨噬细胞和CAF的生长，这可能潜在地参与促进肿瘤生长。我们的结果表明，POSTN可以成为一个有用的预后标志和潜在的治疗靶点。© 2022. The Author(s).

Ovarian cancer has the highest mortality among gynecological cancers due to late diagnosis and lack of effective targeted therapy. Although the study of interplay between cancer cells with their microenvironment is emerging, how ovarian cancer triggers signaling that coordinates with immune cells to promote metastasis is still elusive.Microarray and bioinformatics analysis of low and highly invasive ovarian cancer cell lines were used to reveal periostin (POSTN), a matrix protein with multifunctions in cancer, with elevated expression in the highly invasive cells. Anchorage independent assay, Western blot, RNA interference, confocal analysis and neutralizing antibody treatment were performed to analyze the effects of POSTN on tumor promotion and to explore the underlying mechanism. Chemotaxis, flow cytometry and cytokine array analyses were undertaken to analyze the involvement of POSTN in cancer-associated fibroblast (CAF) and macrophage modulation. Correlations between POSTN expression levels and clinical characteristics were analyzed using the Oncomine, commercial ovarian cancer cDNA and China Medical University Hospital patient cohort. In vivo effect of POSTN on metastasis was studied using a mouse xenograft model.Expression of POSTN was found to be elevated in highly invasive ovarian cancer cells. We observed that POSTN was co-localized with integrin β3 and integrin β5, which was important for POSTN-mediated activation of ERK and NF-κB. Ectopic expression of POSTN enhanced whereas knockdown of POSTN decreased cancer cell migration and invasion in vitro, as well as tumor growth and metastasis in vivo. POSTN enhanced integrin/ERK/NF-κB signaling through an autocrine effect on cancer cells to produce macrophage attracting and mobilizing cytokines including MIP-1β, MCP-1, TNFα and RANTES resulting in increased chemotaxis of THP-1 monocytes and their polarization to M2 macrophages in vitro. In agreement, tumors derived from POSTN-overexpressing SKOV3 harbored more tumor-associated macrophages than the control tumors. POSTN induced TGF-β2 expression from ovarian cancer cells to promote activation of adipose-derived stromal cells to become CAF-like cells expressing alpha smooth muscle actin and fibroblast activation protein alpha. Consistently, increased CAFs were observed in POSTN overexpressing SKOV3 cells-derived metastatic tumors. In clinical relevance, we found that expression of POSTN was positively correlated with advanced-stage diseases and poor overall survival of patients.Our study revealed a POSTN-integrin-NF-κB-mediated signaling and its involvement in enhancing M2 macrophages and CAFs, which could potentially participate in promoting tumor growth. Our results suggest that POSTN could be a useful prognosis marker and potential therapeutic target.© 2022. The Author(s).