Zhang Shuxia, Huang Feichao, Wang Jin, You Ruolan, Huang Qiqi, Chen Yuanzhong
Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
Minimally Invasive Surgery, People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, 350001, China.
Protoplasma. 2025 May;262(3):635-647. doi: 10.1007/s00709-024-02023-z. Epub 2025 Jan 9.
Mantle cell lymphoma (MCL) is a rare, highly invasive non-Hodgkin's lymphoma. The main pathogenesis of MCL is associated with the formation of the IgH/CCND1 fusion gene and nuclear overexpression of cyclin D1, which accelerates the cell cycle, leading to tumorigenesis. The prognosis with current standard chemotherapy is still unsatisfactory. SQSTM1/p62 is a multifunctional adaptor that plays an important role in various tumors. Here, we found that the expression of p62 in MCL tissues was higher than that in hyperplastic lymphadenitis patients. Patients with low p62 expression in MCL cells had better overall survival and progression-free survival rates than those with high expression (p = 0.024 and p = 0.025, respectively). Multivariate Cox analysis indicated that the calculated death risk (hazard ratio [HR]) in patients with high expression levels of p62 increased to 2.742 (95% confidence interval (CI) of 1.268-5.852, p = 0.01), which was higher than those with low levels. Silencing p62 impaired Jeko-1 and Granta519 cell proliferation while downregulating CCND1 mRNA and protein expression, thereby inducing G0/G1 cell cycle arrest. However, silencing p62 does not affect the fusion of IgH and CCND1. Luciferase reporter gene analysis and chromatin immunoprecipitation analysis demonstrated that p62 may regulate CCND1 gene expression through Nrf2. These results provide evidence that p62 can predict poor prognosis in MCL. The precise targeting of p62 therapy reduces the promoting effect of Nrf2 on CCND1, thereby preventing cell cycle progression and effectively inhibiting tumor proliferation. Therefore, p62 may provide a potential target for MCL.
套细胞淋巴瘤（MCL）是一种罕见的、侵袭性很强的非霍奇金淋巴瘤。MCL的主要发病机制与IgH/CCND1融合基因的形成及细胞周期蛋白D1的核内过表达有关，后者加速细胞周期，导致肿瘤发生。目前标准化疗的预后仍不尽人意。SQSTM1/p62是一种多功能衔接蛋白，在多种肿瘤中发挥重要作用。在此，我们发现MCL组织中p62的表达高于增生性淋巴结炎患者。MCL细胞中p62表达低的患者总生存率和无进展生存率高于高表达患者（分别为p = 0.024和p = 0.025）。多因素Cox分析表明，p62高表达患者的计算死亡风险（风险比[HR]）增至2.742（95%置信区间[CI]为1.268 - 5.852，p = 0.01），高于低表达患者。沉默p62会损害Jeko - 1和Granta519细胞的增殖，同时下调CCND1 mRNA和蛋白表达，从而诱导G0/G1期细胞周期阻滞。然而，沉默p62并不影响IgH与CCND1的融合。荧光素酶报告基因分析和染色质免疫沉淀分析表明，p62可能通过Nrf2调节CCND1基因表达。这些结果证明p62可预测MCL的不良预后。精准靶向p62治疗可降低Nrf2对CCND1的促进作用，从而阻止细胞周期进程并有效抑制肿瘤增殖。因此，p62可能为MCL提供一个潜在靶点。
