Portseva T N, Kotnova A P, Bulavkina E V, Makarova A A, Georgieva S G, Stepchenko A G, Pankratova E V
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.
Mol Biol (Mosk). 2022 Jul-Aug;56(4):595-603. doi: 10.31857/S0026898422040097.
Increased expression levels of the Oct-1 transcription factor is considered to be one of the key markers of poor cancer prognosis. In addition to the ubiquitous Oct-1A isoform, which is found in all cells, there also exists a tissue-specific Oct-1L isoform, which is expressed in hematopoietic cells. Oct-1L increases cell resistance to different stresses and also regulates the expression of genes controlling differentiation of hematopoietic and immune system cells. The tissue-specific Oct-1L isoform levels are significantly increased in the B-cell lymphoblastoma Namalwa and Raji lines and the T-cell lymphoblastoma Jurkat line compared to normal B and T cells. Apparently, aberrant Oct-1L overexpression not only enhances stress resistance but also leads to the disruption of developmental pathways in the cells promoting their malignant transformation. We report here that targeted suppression of the tissue-specific Oct-1L isoform expression reduces the proliferation rate of Namalwa B-lymphoblastic Burkitt's lymphoma cells, significantly increases cell death rate under hypoxic conditions, and makes cells more sensitive to chemotherapeutic agents such as docetaxel and doxorubicin. These results indicate that targeted therapy aimed at the suppression of the Oct-1 isoforms with increased expression levels in tumor cells rather than the total Oct-1, thus avoiding the traumatic effects of total Oct-1 knockdown, may be promising. Selective suppression of Oct-1 isoforms is a promising strategy in the treatment of lymphoid tumors and may contribute to mitigating the disease course and increasing survival rates in cancer patients.
Oct-1转录因子表达水平升高被认为是癌症预后不良的关键标志物之一。除了在所有细胞中都存在的普遍存在的Oct-1A亚型外,还存在一种组织特异性的Oct-1L亚型,其在造血细胞中表达。Oct-1L增加细胞对不同应激的抗性,并调节控制造血和免疫系统细胞分化的基因的表达。与正常B细胞和T细胞相比,B细胞淋巴瘤Namalwa和Raji系以及T细胞淋巴瘤Jurkat系中组织特异性Oct-1L亚型水平显著升高。显然,异常的Oct-1L过表达不仅增强了应激抗性,还导致细胞发育途径的破坏,促进其恶性转化。我们在此报告,靶向抑制组织特异性Oct-1L亚型表达可降低Namalwa B淋巴细胞伯基特淋巴瘤细胞的增殖率,在缺氧条件下显著提高细胞死亡率,并使细胞对多西他赛和阿霉素等化疗药物更敏感。这些结果表明,针对肿瘤细胞中表达水平升高的Oct-1亚型而非总Oct-1进行靶向治疗,从而避免总Oct-1敲低的创伤性影响,可能是有前景的。选择性抑制Oct-1亚型是治疗淋巴瘤的一种有前景的策略,可能有助于减轻疾病进程并提高癌症患者的生存率。