NFYB potentiates STK33 activation to promote cisplatin resistance in diffuse large B-cell lymphoma
Introduction
Diffuse large B cell lymphoma (DLBCL) is the most frequent diagnosed type of lymphoma in adults worldwide which constitutes about one-third of all non-Hodgkin lymphoma cases each year, posing a substantial socioeconomic burden disturbing millions of people [1]. There are mainly three subgroups of DLBCL, activated B-cell-like, germinal-center B-cell-like, and unclassified based on the cell of origin that are linked to the response to chemotherapy and targeted agents [2]. For patients with relapsed non-Hodgkin lymphoma with prior anthracycline exposure, the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin) is applicable [3]. However, many patients develop resistance after treatment with standard chemotherapy, making researching the molecular mechanisms of DLBCL to develop effective treatments very important [4].
Serine/threonine kinase 33 (STK33), which was discovered by sequencing the human chromosome 11 region 11p15 and mouse chromosome 7, is expressed in various tissues, including testis, fetal lung and heart, and retina [5]. The overexpression of STK33 has been identified in many solid tumors, involving hypopharyngeal squamous cell carcinoma, lung cancers, and colorectal cancer [[6], [7], [8], [9], [10]]. More recently, STK33-dependent cisplatin resistance has been suggested to promote tumor growth in lung adenocarcinoma [11], implying the close correlation between STK33 expression and cisplatin resistance in cancers. Mechanistically, in gastric cancer, KLF4, a transcription factor, transcriptionally repressed STK33 expression, and gastric cancer cell invasion inhibited by KLF4 was reversed by upregulation of STK33 [12]. As a consequence, we postulated that STK33 regulates cisplatin resistance in DLBCL with the involvement of a transcription factor. In addition, the Hedgehog signaling pathway has been indicated to be activated in DLBCL, which contributed to tumor cell survival and proliferation [13]. The association between the Hedgehog signaling pathway and cisplatin resistance has been highlighted in lung adenocarcinoma and ovarian epithelial tumors [14,15]. In addition, aberrant activation of Hedgehog pathways is ubiquitously observed and established to modulate tumor growth, survival, and chemoresistance in DLBCL [16]. Nevertheless, its implication in DLBCL cisplatin resistance remains to be clarified. Thus, we determined the Hedgehog signaling pathway as the downstream pathway of STK33 in DLBCL.
In the present study, we explored how the alteration in STK33 expression in two DLBCL lines, OCI-Ly1 and SUDHL4, affects cisplatin resistance in vitro and in vivo and the induction of the Hedgehog signaling axis, and elucidated the upstream mechanism of STK33 expression in DLBCL. This study was set to provide a possible and reliable theory for cisplatin resistance in DLBCL.
Section snippets
Microarray analysis
Firstly, we downloaded DLBCL-related gene expression microarrays from the Gene Expression Omnibus (GEO) databases (http://www.ncbi.nlm.nih.gov/geo/): GSE57520 (containing three spleen tissues and four lymphoma tissues), GSE27255 (containing eight parental cells and six drug-resistant lymphoma cell lines), and GSE61516 (containing four parental cells and 20 doxorubicin-resistant lymphoma cells). The gene expression profiling was conducted using the Affymetrix Human Genome U133 Plus 2.0 array
STK33 is significantly associated with the development and drug resistance in DLBCL
First, we downloaded the DLBCL-related gene expression microarrays from the GEO database. We normalized and corrected the data using R Limma package and analyzed the differentially expressed genes. A total of 76, 193 and 297 differentially expressed genes were screened out, respectively (Fig. 1A-C). Four genes, STK33, AIG1, TET2, and MYBPH were found in the intersection (Fig. 1D). Then, we searched the expression of these four genes in the TCGA-DLBC database, and we found a significant
Discussion
In this study, we examined the underlying molecular basis for STK33 overexpression in DLBCL and delineated its function in cisplatin resistance. We found that expression of STK33 was frequently higher in tumors than in adjacent tissue. We also exhibited a positive correlation between STK33 expression and cisplatin resistance in DLBCL cells. In vitro and in vivo experiments demonstrated that STK33 expedited DLBCL cell resistance to cisplatin by activating the Hedgehog pathway, as evidenced by
Conclusion
In conclusion, we found here in the study that there was an overexpression of STK33 in DLBCL cell lines. Moreover, ectopic expression of STK33 induced by NFYB promoted the cisplatin resistance of DLBCL cells by activating the Hedgehog signaling. Our study may possibly provide a theoretical basis for overcoming cisplatin resistance in DLBCL.
Funding
This work was supported by National Natural Science Foundation of China (81900876).
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgement
The authors are thankful to National Natural Science Foundation of China (81900876).
References (28)
- et al.
STK33 overexpression in hypopharyngeal squamous cell carcinoma: possible role in tumorigenesis
BMC Cancer
(2015) - et al.
MicroRNA-182-5p regulates hedgehog signaling pathway and chemosensitivity of cisplatin-resistant lung adenocarcinoma cells via targeting GLI2
Cancer Lett.
(2020) - et al.
Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-kappaB activation in diffuse large B-cell lymphoma
Blood
(2013) - et al.
Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity
Blood
(2010) - et al.
Transcriptional regulation of serine/threonine protein kinase (AKT) genes by glioma-associated oncogene homolog 1
J. Biol. Chem.
(2013) - et al.
Smoothened stabilizes and protects TRAF6 from degradation: a novel non-canonical role of smoothened with implications in lymphoma biology
Cancer Lett.
(2018) - et al.
NFYB-induced high expression of E2F1 contributes to oxaliplatin resistance in colorectal cancer via the enhancement of CHK1 signaling
Cancer Lett.
(2018) - et al.
New agents and regimens for diffuse large B cell lymphoma
J. Hematol. Oncol.
(2020) - et al.
Genetics and pathogenesis of diffuse large B-cell lymphoma
N. Engl. J. Med.
(2018) - et al.
Pixantrone beyond monotherapy: a review
Ann. Hematol.
(2019)
Genetic and epigenetic determinants of diffuse large B-cell lymphoma
Blood Cancer J.
STK33 promotes hepatocellular carcinoma through binding to c-Myc
Gut
Knockdown of human serine/threonine kinase 33 suppresses human small cell lung carcinoma by blocking RPS6/BAD signaling transduction
Neoplasma
STK33 plays an important positive role in the development of human large cell lung cancers with variable metastatic potential
Acta Biochim Biophys Sin (Shanghai)
Cited by (8)
Expression and function of NF-Y subunits in cancer
2024, Biochimica et Biophysica Acta - Reviews on CancerThe Nup98::Nsd1 fusion gene induces CD123 expression in 32D cells
2023, International Journal of Hematology