Caetano Mônica Maria Magalhães, Moreira Gabriela Alves, da Silva Maria Roméria, Guimarães Gabriela Rapozo, Santos Leandro de Oliveira, Pacheco Amanda de Ambrósio, Siqueira Raoni Pais, Mendes Flávia Carneiro, Marques Da Silva Eduardo De Almeida, Junior Abelardo Silva, Rangel Fietto Juliana Lopes, Saito Ângela, Boroni Mariana, Bressan Gustavo Costa
Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa (UFV), Viçosa, Brazil.
Laboratório de Bioinformática e Biologia Computacional, Divisão de Pesquisa Experimental e Translacional, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil.
Front Genet. 2022 Sep 23;13:979735. doi: 10.3389/fgene.2022.979735. eCollection 2022.
Melanoma is one of the most aggressive tumors, and its lethality is associated with the ability of malignant cells to migrate and invade surrounding tissues to colonize distant organs and to generate widespread metastasis. The serine/arginine protein kinases 1 and 2 (SRPK1 and SRPK2) are classically related to the control of pre-mRNA splicing through SR protein phosphorylation and have been found overexpressed in many types of cancer, including melanoma. Previously, we have demonstrated that the pharmacological inhibition of SRPKs impairs pulmonary colonization of metastatic melanoma in mice. As the used compounds could target at least both SRPK1 and SRPK2, here we sought to obtain additional clues regarding the involvement of these paralogs in melanoma progression. We analyzed single-cell RNA sequencing data of melanoma patient cohorts and found that SRPK2 expression in melanoma cells is associated with poor prognosis. Consistently, CRISPR-Cas9 genome targeting of SRPK2, but not SRPK1, impaired actin polymerization dynamics as well as the proliferative and invasive capacity of B16F10 cells . In further experiments, genetic targeting of SRPK2, but not SRPK1, reduced tumor progression in both subcutaneous and caudal vein melanoma induction models. Taken together, these findings suggest different functional roles for SRPK1/2 in metastatic melanoma and highlight the relevance of pursuing selective pharmacological inhibitors of SRPK2.
黑色素瘤是最具侵袭性的肿瘤之一，其致死性与恶性细胞迁移和侵袭周围组织以在远处器官定植并产生广泛转移的能力有关。丝氨酸/精氨酸蛋白激酶1和2（SRPK1和SRPK2）传统上与通过SR蛋白磷酸化控制前体mRNA剪接有关，并且已发现在包括黑色素瘤在内的多种癌症中过表达。此前，我们已经证明，对SRPKs的药理学抑制会损害小鼠转移性黑色素瘤的肺定植。由于所使用的化合物可能至少靶向SRPK1和SRPK2两者，因此我们在此寻求获得有关这些旁系同源物参与黑色素瘤进展的更多线索。我们分析了黑色素瘤患者队列的单细胞RNA测序数据，发现黑色素瘤细胞中SRPK2的表达与预后不良有关。一致地，对SRPK2而非SRPK1进行CRISPR-Cas9基因组靶向，会损害肌动蛋白聚合动力学以及B16F10细胞的增殖和侵袭能力。在进一步的实验中，对SRPK2而非SRPK1进行基因靶向，在皮下和尾静脉黑色素瘤诱导模型中均降低了肿瘤进展。综上所述，这些发现表明SRPK1/2在转移性黑色素瘤中具有不同的功能作用，并突出了寻求SRPK2选择性药理学抑制剂的相关性。
