FL represents the second most common form of NHL with high rates of HTs. Once treated inappropriately, FL would be transformed into tFL or DLBCL, leading to a poorer prognosis[10, 34]. Previous studies have shown that most of the oncogenic transformations are initiated primarily through intracellular gene mutation. Among them, the several kinase coding genes integration into human transcription and expression of the several families of kinases proteins tyrosine kinases, aurora kinases, cycle-dependent kinases, and mTOR, as well as mitogen-activated protein kinases (MAPK), have been the classic driver mechanism for kinase-mediated oncogenic cell transformations[35].
Using FL tissue as a control, the current study is one of the few pieces of research that integrates transcriptomic bioinformatics analysis in HTs patients with relatively large sample size. When considering the impact of biological behavior on the HTs of patients with FL, the intersection of functions enrichment analysis results of DEGs in HTs samples performed that its mediated functions may be closely associated with the cell division, immune response, mitotic spindle organization, and chromosome segregation of BPs, extracellular space, extracellular region, and external side of the plasma membrane of CCs, and protein binding, microtubule-binding, heparin-binding of MFs, and cytokine-cytokine receptor interaction, chemokine signaling pathway, and viral protein interaction with cytokine and cytokine receptor signaling pathway of KEGG. Subsequently, the 10 hub genes were screened as prognostic biomolecular markers by further constructing an overlapping PPI network, and the gene range was reduced by exploring the potential TFs regulatory networks and drug-gene interactions in other public repositories. Finally, it was determined that 3 hub genes (CDK1, RRM2, and AURKA) could be applied to pivotal prognostic molecular markers and therapeutic targets of FL.
Studies have shown that CDK1, also known as cell division cycle 2 (CDC2) and is one of the key genes associated with regulating the G2/M phase transition and activates the homologous recombination DNA repair pathway in cell regulation cycle progression [36]. Furthermore, the abnormal expression of CDK1 plays an oncogenic role in promoting tumorigenesis in patients with lung cancer, mammary carcinoma, pancreatic ductal carcinoma, hepatocellular carcinoma, melanoma, gastric cancer, colorectal cancer, endometrioid endometrial cancer, gastrointestinal stromal tumor, prostate cancer, epithelial ovarian cancer, and cutaneous squamous cell carcinoma and is associated with development, cell differentiation disorders, cell cycle disorders, malignant proliferation, and transformation[37–50]. RRM2 serves as the catalytic subunit of ribonucleotide reductase and is an important rate-limiting enzyme involved in DNA synthesis, and damage repair, and its relative abundance is associated with DNA replication, and cell proliferation, invasiveness, migration, senescence, metastasis, cancer grade level, and translation[51–56]. In addition, RRM2 is also a tumor driver, and the frequently up-regulated in non-small cell lung cancer, adrenocortical cancer, colorectal cancer, and breast cancer are correlated with a worse prognosis[54,57−60]. Moreover, silencing of RRM2 attenuated melanoma growth, which was consistent with the maintenance of senescence-associated cell-cycle arrest[61]. The AURKA is one of the key serine/threonine kinases associated with biological processes of mitosis and other non-mitosis activities, and is most expressed during the G2/M phase of the cell cycle and regulates the activation of PLK1, which is a crucial step for checkpoint recovery[62, 63]. Surprisingly, AURKA is frequently amplified and overexpressed by causing the inactivation of the DNA damage checkpoint during the G2 phase, the inactivation of the spindle assembly checkpoint during mitosis, chromosomal abnormalities, and instability of the cell genome[62, 64, 65]. Indeed, the up-regulation of AURKA in several malignancies patients is related to a poorer prognosis. Furthermore, high expression of AURKA also induces the mutation of the tumor suppressors like p21, p53, or retinoblastoma and the activation of the oncogenic factors like c-MYC, NF-kB, or β-Catenin as well as the deregulation of multiple cancer-related signaling pathways like TP53, mTOR, Hippo, PI3K-Akt, WNT, ERK1/2 alongside with FOXO and Ras-MAPK as well as NF-κB genes through stopping apoptosis and enhancing cancer cell proliferation, cell survival, genomic instability, epithelial-mesenchymal transition, metastasis, self-renewal of cancer stem cells, plasticity, chemo/drug-resistance, oncogenic transformation, cancer stem cell phenotype, and inhibiting cancer cell apoptosis, promoting tumorigenesis and progression[66–76]. Moreover, in relapsed/refractory aggressive B-cell Lymphoma, patients with overexpression and/or amplification of AURKA related to tumor progression and poor patient outcomes[78]. AURKA inhibitor has presented preclinical synergy effects on the immunochemotherapy of DLBCL with rituximab and vincristine. At the same time, silencing AURKA reinforces the sensitivity of DLBCL neoplastic cells to CHOP by inhibiting β-catenin and the RAS-ERK1/2 pathway[70, 77].