Decreasing of serine/threonine kinase 39 has tumour inhibiting effects on acute myeloid leukaemia by impacting the PI3K/AKT and Wnt/ß-catenin signalling cascades.

Serine/threonine kinase 39 (STK39) has been identified as a key regulator of tumour progression. However, whether STK39 plays a role in acute myeloid leukaemia (AML) remains undetermined. This work explored the expression and functions of STK39 in AML. STK39 was found to be overexpressed in AML and was negatively correlated with overall survival. Functionally, silencing STK39 inhibited cell proliferation, promoted cell differentiation and induced cell cycle arrest and apoptosis. The tumour inhibiting effects of STK39 downregulation were also verified by an in vivo xenograft tumour assay. Mechanistically, STK39 was closely related to the PI3K/AKT and Wnt/ß-catenin signalling cascades in AML. Silencing of STK39 had suppressive effects on the PI3K/AKT and Wnt/ß-catenin signalling cascades. The suppressive effect of STK39 silencing on the Wnt/ß-catenin signalling cascade was significantly reversed when PI3K/AKT was reactivated. When ß-catenin was re-expressed, the tumour-inhibiting effects caused by STK39 silencing were significantly eliminated. Therefore, STK39 plays a crucial role in AML and could be targeted for potential therapeutic purposes in treating AML.

Downregulation of circ-STK39 suppresses pancreatic cancer progression by sponging mir-140-3p and regulating TRAM2-mediated epithelial-mesenchymal transition.

BACKGROUND: Pancreatic cancer (PC) is amongst the most lethal gastrointestinal tumors, which is the seventh leading reason of cancer-related mortality worldwide. Previous studies have indicated that circular RNAs (circRNAs), which is a new type of endogenous noncoding RNA (ncRNA), can mediate tumor progression in diverse tumor types including PC. Whereas precise roles regarding circRNAs and their underlying regulatory mechanisms in PC remain unknown. METHODS: In the current study, we employed next generation sequencing (NGS) to characterize abnormally expressed circRNAs among PC tissues. Next, we assessed expression levels of one identified circRNA, circ-STK39, in PC cell lines and tissues. Then, using bioinformatics analysis, luciferase reporter, Transwell migration, EdU and CCK-8 assays, we examined the regulatory mechanisms and targets of circ-STK39. Finally, our group explored the circ-STK39 role in PC tumor growth and metastasis in vivo. RESULTS: Our team discovered that circ-STK39 expression increased in PC tissues and cells, suggesting that circ-STK39 may have a role in PC progression. Downregulation of circ-STK39 inhibited PC proliferation and migration. Bioinformatics and luciferase reporter outcomes demonstrated that TRAM2 and miR-140-3p were circ-STK39 downstream targets. TRAM2 overexpression reversed the miR-140-3p overexpression effects upon migration, proliferation and the epithelial-mesenchymal transition (EMT). CONCLUSION: In this regard, we showed that circ-STK39 downregulation led to decreased migration, proliferation and the EMT of PC via the miR-140-3p/TRAM2 axis.

Gut microbiota-induced microRNA-206-3p increases anxiety-like behaviors by inhibiting expression of Cited2 and STK39.

BACKGROUND: Anxiety disorder is highly prevalent worldwide and represents a chronic and functionally disabling condition, with high levels of psychological stress characterized by cognitive and physiological symptoms. The purpose of this study is to evaluate the clinical significance of gut microbiota regulating microRNA (miR)-206-3p as a biomarker in the anxiety-like behaviors. METHODS: Initially, bioinformatics analysis was performed to predict the related factors for gut microbiota affecting anxiety-like behaviors. Next, the anxiety-like behaviors in mice were measured by multiple experiments. Western blot analysis, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were utilized to measure the levels of 5-hydroxytryptamine (5-HT), brain derived neurotrophic factor (BDNF), and neutrophil expressed (NE) in brain tissues and serum and cAMP responsive element binding protein 1 (CREB) phosphorylation in brain tissues of germ-free (GF) mice. Dual-luciferase reporter gene assay was employed to verify the relationship between miR-206-3p and Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (Cited2)/serine/threonine kinase 39 (STK39). Ectopic expression and depletion experiments of miR-206-3p were conducted to determine the expression of miR-206-3p and mRNA and protein levels of Cited2, and STK39 in HT22 cells and brain tissues. Finally, transmission electron microscope (TEM) was used to observe the effects of miR-206-3p on hippocampal mitochondria and synapses. RESULTS: Gut microbiota could elevate miR-206-3p expression in brain tissues to increase the anxiety-like behaviors. GF mice displayed the increased levels of 5-HT, BDNF, and NE in brain tissues and serum and CREB phosphorylation in brain tissues. Cited2/STK39 was identified as the target genes of miR-206-3p. Upregulated miR-206-3p increased anxiety-like behaviors by promoting degeneration of mitochondria and synapses in hippocampus via downregulation of Cited2 and STK39. CONCLUSIONS: In conclusion, the key findings of the current study demonstrate that gut microbiota aggravated anxiety-like behaviors via the miR-206-3p/Cited2/STK39 axis.

Positive association between ATP2B1 rs17249754 and essential hypertension: a case-control study in Burkina Faso, West Africa.

BACKGROUND: Genetic and environment play a significant role in the etiology of essential hypertension (EH). Recently STK39 rs3754777, ATP2B1 rs2681472 and rs17249754 have been associated with BP variation and hypertension. In this study we aimed to determine firstly whether index variants were associated with the risk of developing EH in Burkina Faso and secondly to characterize cardiovascular risk markers. METHODS: We conducted a case-control study with 380 participants including 180 case subjects with EH and 200 control subjects with normal BP. We used TaqMan genotyping assays with probes from Applied Biosystems to genotype polymorphisms using the 7500 Real-Time PCR System. Biochemical parameters were measured using chemistry analyzer COBAS C311. RESULTS: T-test showed that cardiovascular risk markers such as body mass index, waist circumference, blood sugar, total cholesterol and triglycerides were significantly higher in hypertensive compared to normotensive (all p <  0.05). Binary logistic regression analysis revealed in decreasing order that overweight, family history of hypertension, central obesity and alcohol intake increased the risk of developing EH (all OR > 3.8; all p <  0.001). In genetic level we observed that individuals carrying the AA+AG genotype of ATP2B1 rs17249754 had a low risk of developing EH than those carrying the GG genotype (OR = 0.48 [95% CI: 0.31-0.75] p = 0.001) and the A allele frequency in the cases was significantly lower than that of the controls (OR = 0.56 [95% CI: 0.38-0.82] p = 0.003). We also observed that ATP2B1 rs17249754 was significantly associated with higher SBP and DPB in case and control groups (GG versus AG + AA; p <  0.05), ATP2B1 rs2681472 was significantly associated with higher SBP only in case and control group (AA versus AG + GG; p <  0.05), STK39 rs3754777 was not significantly associated with any of the BP traits (CC versus CT + TT; p > 0.05). CONCLUSION: Our results confirmed the significant association of ATP2B1 rs17249754 with the risk of developing EH in Burkinabe and showed an increase of cardiovascular risk markers levels in subjects with EH.

Type 2 diabetes-related proteins derived from an in vitro model of inflamed fat tissue.

Currently, there is a worldwide increase of patients with type 2 diabetes (T2D). During the progression of healthy obese to T2D status, there is an influx of immune cells, in particular macrophages, into visceral adipose tissue, accompanied by an increase of inflammatory cytokines, such as, IL6, TNFα and Hp. To get a better insight in the underlying mechanisms, we performed a quantitative LCMS analysis on a modified in vitro assay, combining 3T3L1 adipocytes and activated RAW264.7 macrophages, thus mimicking inflamed adipose tissue. Clinically known proteins, e.g. IL6, TNFα, AdipoQ, complement factor C3, B and D were identified, thus confirming the assay. In addition, we found 54 new proteins that can potentially be used for research into the mechanism of T2D. Comparison of our results to a study on human visceral fat of obese non-diabetic and obese diabetic subjects, indicated that AUH, NAGK, pCYT2, NNMT, STK39 and CSNK2A2 might indeed be linked to insulin resistance in humans. Moreover, the expression of some of these genes was also altered in human blood samples at early or later stages of insulin desensitization. Overall, we conclude that the direct contact co-culture of 3T3L1 adipocytes with activated macrophages could be a mechanistically relevant and partially translational model of inflamed visceral adipose tissue.

WNK pathways in cancer signaling networks.

BACKGROUND: The with no lysine [K] (WNK) pathway consists of the structurally unique WNK kinases, their downstream target kinases, oxidative stress responsive (OSR)1 and SPS/Ste20-related proline-alanine-rich kinase (SPAK), and a multitude of OSR1/SPAK substrates including cation chloride cotransporters. MAIN BODY: While the best known functions of the WNK pathway is regulation of ion transport across cell membranes, WNK pathway components have been implicated in numerous human diseases. The goal of our review is to draw attention to how this pathway and its components exert influence on the progression of cancer, specifically by detailing WNK signaling intersections with major cell communication networks and processes. CONCLUSION: Here we describe how WNKs and associated proteins interact with and influence PI3K-AKT, TGF-ß, and NF-κB signaling, as well as its unanticipated role in the regulation of angiogenesis.

ATP2B1 rs2681472 and STK39 rs35929607 polymorphisms and risk of Hypertension in Iranian Population.

Background: ATP2B1 and STK39 have been introduced as essential hypertension candidate genes. The association of these genes' variations have not been studied in Iranian population yet. Here we aimed to investigate the association of ATP2B1 rs2681472 and STK39 rs35929607 polymorphisms with the risk of hypertension in an Iranian population. Methods: We included 400 individuals in our case-control study: 200 cases with essential hypertension and 200 healthy sex and age matched controls. All subjects were genotyped for rs2681472 and rs35929607 using a PCR-RFLP method. Genotype and allele frequencies were compared between the two groups using chi-squared test. The association was further assessed under log-additive, dominant and recessive genetic models. Results: There was no association between rs2681472 and rs35929607 polymorphisms and risk of essential hypertension in our population (p>0.05). There was also no association between the studied polymorphisms and hypertension under different genetic models. Conclusion: Our study indicated that rs2681472 of ATP2B1 and rs35929607 of STK39 may not have a significant effect on the risk of essential hypertension in Iranian population. More studies are still needed to validate our results.

Association of three candidate genetic variants in RAB7L1/NUCKS1, MCCC1 and STK39 with sporadic Parkinson's disease in Han Chinese.

Previous studies identified that polymorphisms RAB7L1/NUCKS1 rs823118, MCCC1 rs12637471 and STK39 rs1955337 to be the risk loci for Parkinson's disease (PD) in a Caucasian population. However, the characteristics of these three polymorphisms in a Han Chinese population from mainland China were unknown. We examined genetic associations of rs823118, rs12637471 and rs1955337 with PD susceptibility in a Han Chinese population of 1016 sporadic PD patients and 1069 controls. We also conducted further stratified analysis according to age at onset and compared the clinical characteristics between minor allele carriers and non-carriers for each locus. In this study, the minor allele frequency (MAF) was significantly different of RAB7L1/NUCKS1 rs823118 (P = 0.003) and MCCC1 rs12637471 (P = 0.008) between cases and controls. Subjects of RAB7L1/NUCKS1 rs823118 with CC+CT genotypes had a decreased risk compared to those with TT genotype (P = 0.001) and this association also can be seen among younger population (<50 years, P = 0.011). For the MCCC1 rs12637471, subjects with GA+GG genotypes had an increased risk compared to those with AA genotype (P = 0.017). However, we did not observe any significant difference in allele and genotype distribution between PD patients and controls for rs1955337 in STK39. In addition, minor allele carriers cannot be distinguished from non-carriers based on their clinical features of the three loci. Our study provides strong support for the susceptibility role of rs823118 and rs12637471 in sporadic PD in a Han Chinese population.

Suppression of STK39 weakens the MASLD/MASH process by protecting the intestinal barrier.

STK39 is reportedly a critical negative regulator of intestinal barrier. Pharmacological targeting of STK39 is expected to protect the intestinal barrier and thereby weaken metabolic dysfunction-associated steatohepatitis (MASH); Proximal colon biopsy tissues from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and those without MASLD were analyzed for STK39 expression. Wildtype (WT) mice and systemic STK39 gene knockout (STK39-/-) male mice were fed a normal diet or a high-fat methionine-choline deficient diet (HFMCD) for 8 weeks. The MASH mice were grouped and treated with ZT-1a (a STK39 inhibitor) or vehicle intraperitoneal injection during the procedure of HFMCD induction. Liver and intestinal tissues were collected for further examination; Colon tissues from patients with MASLD exhibited higher levels of STK39 than those from subjects without MASLD. Knockout of STK39 diminished CD68+ Kupffer cells and α-SMA+ hepatic stellate cells infiltration in mouse MASH model. Treatment with ZT-1a also prevented severe steatohepatitis in a mouse MASH model, including milder histological and pathological manifestations (lobular inflammation and fibrosis) in the liver. Interestingly, Inhibition of STK39 had minimal effects on hepatic lipid metabolism. The reduced liver injury observed in mice with STK39 inhibition was linked to significant decreases in mucosal inflammation, tight junction disruption and intestinal epithelial permeability to bacterial endotoxins; Collectively, we have revealed that inhibiting STK39 prevents the progression of MASH by protecting the intestinal epithelial barrier.

Cross-border regulation of the STK39/MAPK14 pathway by Lycium barbarum miR166a to inhibit triple-negative breast cancer.

OBJECTIVE: To investigate the effects of Lycium barbarum miRNA166a (Lb-miR166a) on human gene expression regulation during the therapy for triple-negative breast cancer (TNBC). METHODS: Transcriptome sequencing was used to analyze the distribution and composition of miRNA in Lycium barbarum fruit. Lb-miR166a was introduced into TNBC MB-231 cells by lentiviral transfection to study its effects on cell proliferation, apoptosis, invasion, and metastasis both in vivo and in vitro. Bioinformatic and dual-luciferase assays identified the target gene of Lb-miR166a. The role of STK39 in TNBC progression was elucidated through clinical data analysis combined with cellular studies. The influence of Lb-miR166a on the STK39/MAPK14 pathway was confirmed using a target-specific knockout MB-231 cell line. RESULTS: Lb-miR166a was found to be highly expressed in Lycium barbarum. It inhibited MB-231 cell proliferation, invasion, and metastasis, and promoted apoptosis. STK39 was overexpressed in TNBC and was associated with increased invasiveness and poorer patient prognosis. Gene enrichment analysis and dual-luciferase assays demonstrated that Lb-miR166a regulates STK39 expression cross-border and inhibits MAPK14 phosphorylation, impacting the phosphorylation of downstream target genes. CONCLUSION: The downregulation of STK39 and subsequent inhibition of MAPK14 phosphorylation by Lb-miR166a leads to reduced proliferation, migration, and invasion of TNBC cells. These findings suggest a novel therapeutic strategy for TNBC treatment, highlighting possible clinical applications of Lb-miR166a in managing this aggressive cancer type.

The Ubiquitin-Proteasome System Participates in Sperm Surface Subproteome Remodeling during Boar Sperm Capacitation.

Sperm capacitation is a complex process endowing biological and biochemical changes to a spermatozoon for a successful encounter with an oocyte. The present study focused on the role of the ubiquitin-proteasome system (UPS) in the remodeling of the sperm surface subproteome. The sperm surface subproteome from non-capacitated and in vitro capacitated (IVC) porcine spermatozoa, with and without proteasomal inhibition, was selectively isolated. The purified sperm surface subproteome was analyzed using high-resolution, quantitative liquid chromatography-mass spectrometry (LC-MS) in four replicates. We identified 1680 HUGO annotated proteins, out of which we found 91 to be at least 1.5× less abundant (p < 0.05) and 141 to be at least 1.5× more abundant (p < 0.05) on the surface of IVC spermatozoa. These proteins were associated with sperm capacitation, hyperactivation, metabolism, acrosomal exocytosis, and fertilization. Abundances of 14 proteins were found to be significantly different (p < 0.05), exceeding a 1.5-fold abundance between the proteasomally inhibited (100 µM MG132) and vehicle control (0.2% ethanol) groups. The proteins NIF3L1, CSE1L, NDUFB7, PGLS, PPP4C, STK39, and TPRG1L were found to be more abundant; while BPHL, GSN, GSPT1, PFDN4, STYXL1, TIMM10, and UBXN4 were found to be less abundant in proteasomally inhibited IVC spermatozoa. Despite the UPS having a narrow range of targets, it modulated sperm metabolism and binding by regulating susceptible surface proteins. Changes in CSE1L, PFDN4, and STK39 during in vitro capacitation were confirmed using immunocytochemistry, image-based flow cytometry, and Western blotting. The results confirmed the active participation of the UPS in the extensive sperm surface proteome remodeling that occurs during boar sperm capacitation. This work will help us to identify new pharmacological mechanisms to positively or negatively modulate sperm fertilizing ability in food animals and humans.

STK39 promotes breast cancer invasion and metastasis by increasing SNAI1 activity upon phosphorylation.

SNAI1 is widely regarded as a master driver of epithelial-mesenchymal transition (EMT) and associated with breast cancer progression and metastasis. This pro-malignant role is strongly linked to posttranslational modification, especially phosphorylation, which controls its protein levels and subcellular localization. While multiple kinases are implicated in regulation of SNAI1 stability, the precise mechanism by which SNAI1 is stabilized in tumors remains to be fully elucidated. Methods: A series of in vitro and in vivo experiments were conducted to reveal the regulation of SNAI1 by Serine/Threonine Kinase 39 (STK39) and the role of STK39 in breast cancer metastasis. Results: We identified STK39, a member of Stem 20-like serine/threonine kinase family, as a novel posttranslational regulator that enhances the stability of SNAI1. Inhibition of STK39 via knockdown or use of a specific inhibitor resulted in SNAI1 destabilization. Mechanistically, STK39 interacted with and phosphorylated SNAI1 at T203, which is critical for its nuclear retention. Functionally, STK39 inhibition markedly impaired the EMT phenotype and decreased tumor cell migration, invasion, and metastasis both in vitro and in vivo. These effects were rescued by ectopic SNAI1 expression. In addition, depletion of STK39 dramatically enhanced sensitivity to chemotherapeutic agents. Conclusions: Our study demonstrated that STK39 is a key mediator of SNAI1 stability and is associated with the pro-metastatic cellular process, highlighting the STK39-SNAI1 signaling axis as promising therapeutic targets for treatments of metastatic breast cancer.

Knockdown of STK39 suppressed cell proliferation, migration, and invasion in hepatocellular carcinoma by repressing the phosphorylation of mitogen-activated protein kinase p38.

Hepatocellular carcinoma (HCC) is a serious malignant tumor of the liver. It has been reported that serine/threonine kinase 39 (STK39) participates in tumorigenesis. However, the role of STK39 in HCC remains unknown. In this study, the qRT-PCR and western blot assay demonstrated that STK39 expression was enhanced in HCC patients and tissues. Moreover, CCK-8 and colony formation assays confirmed that knockdown of STK39 suppressed SK-HEP-1 and Huh7 cells proliferation. Furthermore, wound healing assay and transwell assay revealed that knockdown of STK39 repressed SK-HEP-1 and Huh7 cells migration and invasion. Interestingly, knockdown of STK39 reduced p-p38/p38 ratio and levels of c-Myc. Consistently, knockdown of STK39 inhibited the HCC tumor growth in vivo. In summary, knockdown of STK39 suppressed the proliferation, migration, and invasion of HCC cells by inducing the lower levels of p-p38, which might provide a novel therapeutic target for HCC.

STK39 is a novel kinase contributing to the progression of hepatocellular carcinoma by the PLK1/ERK signaling pathway.

Rationale: Protein kinases are critical therapeutic targets for curing hepatocellular carcinoma (HCC). As a serine/threonine kinase, the potential roles of serine/threonine kinase 39 (STK39) in HCC remain to be explored. Methods: The expression of STK39 was examined by RT-qPCR, western blotting and immunohistochemistry. Cell proliferation and apoptosis were detected by CCK8 and TUNEL kit. Cell migration and invasion assays were performed using a transwell system with or without Matrigel. RNA-seq, mass spectrometry and luciferase reporter assays were used to identify STK39 binding proteins. Results: Here, we firstly report that STK39 was highly overexpressed in clinical HCC tissues compared with adjacent tissues, high expression of STK39 was induced by transcription factor SP1 and correlated with poor patient survival. Gain and loss of function assays revealed that overexpression of STK39 promoted HCC cell proliferation, migration and invasion. In contrast, the depletion of STK39 attenuated the growth and metastasis of HCC cells. Moreover, knockdown of STK39 induced the HCC cell cycle arrested in the G2/M phase and promoted apoptosis. In mechanistic studies, RNA-seq revealed that STK39 positively regulated the ERK signaling pathway. Mass spectrometry identified that STK39 bound to PLK1 and STK39 promoted HCC progression and activated ERK signaling pathway dependent on PLK1. Conclusions: Thus, our study uncovers a novel role of STK39/PLK1/ERK signaling axis in the progress of HCC and suggests STK39 as an indicator for prognosis and a potential drug target of HCC.

Knockdown of long non-coding RNA CDKN2B-AS1 suppresses the progression of breast cancer by miR-122-5p/STK39 axis.

The lncRNAs have been made certain to take part in the development of most cancers in multiple ways. Here, our purpose is to making observation of the biological role and function of lncRNA CDKN2B-AS1 in human breast cancer. Twenty-eight pairs of breast cancer tissue and adjacent normal tissue from breast cancer patients were used to investigate the expression of CDKN2B-AS1 by qRT-PCR. And a lentivirus-shRNA guided CDKN2B-AS1 were to reduce its expression. The function of CDKN2B-AS1 was analyzed using a series of in vitro assays. Meanwhile, the xenograft model was used to further explicate the role of CDKN2B-AS1 in breast cancer. As for the results, there is a relative rich expression of CDKN2B-AS1 in breast cancer tissues compared with the corresponding adjacent normal tissues. Compared with the human breast epithelial cell line, the abundant expression of CDKN2B-AS1 in breast cancer cells were revealed as well. Then, knockdown CDKN2B-AS1 inhibited the malignant biological behaviors of MCF7 and T47D cells. In mechanism, CDKN2B-AS1 sponged the miR-122-5p to regulate STK39 expression. Furthermore, the inhibition effect with sh-CDKN2B-AS1 on breast cancer cells was alleviated by miR-122-5p inhibitor. Last, an in vivo model also confirmed that knockdown CDKN2B-AS1 retarded the growth of breast cancer. Our data concluded that knockdown of CDKN2B-AS1 suppresses the progression of breast cancer by miR-122-5p/STK39 axis.

Identification and characterization of alternative STK39 transcripts within human and mouse kidneys reveals species-specific regulation of blood pressure.

STK39 encodes a serine threonine kinase, SPAK, which is part of a multi-kinase network that determines renal Na+ reabsorption and blood pressure (BP) through regulation of sodium-chloride co-transporters in the kidney. Variants within STK39 are associated with susceptibility to essential hypertension, and constitutively active SPAK mice are hypertensive and hyperkalemic, similar to familial hyperkalemic hyperkalemia in humans. SPAK null mice are hypotensive and mimic Gitelman syndrome, a rare monogenic salt wasting human disorder. Mice exhibit nephron segment-specific expression of full length SPAK and N-terminally truncated SPAK isoforms (SPAK2 and KS-SPAK) with impaired kinase function. SPAK2 and KS-SPAK function to inhibit phosphorylation of cation co-transporters by full length SPAK. However, the existence of orthologous SPAK2 or KS-SPAK within the human kidney, and the role of such SPAK isoforms in nephron segment-specific regulation of Na+ reabsorption, still have not been determined. In this study, we examined both human and mouse kidney transcriptomes to uncover novel transcriptional regulation of STK39. We established that humans also express STK39 transcript isoforms similar to those found in mice but differ in abundance and are transcribed from human-specific promoters. In summary, STK39 undergoes species-specific transcriptional regulation, resulting in differentially expressed alternative transcripts that have implications for the design and testing of novel SPAK-targeting antihypertensive medications.

Association of with-no-lysine kinase 1 and Serine/Threonine kinase 39 gene polymorphisms and haplotypes with essential hypertension in Tibetans.

Tibetans have a higher essential hypertension prevalence compared with other ethnics in China. The reason might be due to their unique environmental influence, as well as genetic factor. However, limited studies focus on Tibetan genetics and its association with hypertension. The aim of this study was to investigate the association between With-No-Lysine (K) Kinase 1 (WNK1), Serine/Threonine kinase 39(STK39) genes variants and hypertension in the Tibetan population. 204 Tibetan hypertensive patients and 305 normotensive controls were recruited in an epidemiological survey conducted at 2 sites in the Ganzi Tibetan autonomous region. Patients were genotyped for nineteen WNK1 candidate tag single nucleotide polymorphisms (SNPs) and three STK39 SNPs, and haplotype analysis was performed. Results showed that the allele A in rs1468326 was overrepresented in hypertensive patients versus control (53.4% vs 42.9%, P < 0.05). The multivariable-adjusted odds ratio (OR) for hypertension among CA + AA genotypes carriers was 1.60 (95% CI: 1.02-2.62, P < 0.05), and they also had a higher systolic blood pressure (136.5 ± 28.6 vs 131.7 ± 24.8 mmHg, P < 0.05). However, the TT genotype ratio in rs6749447 was lower in hypertensives (5.4% vs 10.8%, P < 0.05), and the hypertension risk for the TT genotype carriers in rs6749447 decreased after adjustment (OR 0.49, 95% CI 0.19-0.95, P < 0.05). Subjects with haplotype AGACAGGAATCGT showed 1.57 times higher risk of hypertension (95% CI 1.02-2.41, P < 0.05). In conclusion, SNP rs1468326 of WNK1, rs6749447 of STK39, and WNK1 haplotype AGACAGGAATCGT were associated with hypertension in Tibetan individuals. Environ. Mol. Mutagen. 59:151-160, 2018. © 2017 Wiley Periodicals, Inc.

STK39 blockage by RNA interference inhibits the proliferation and induces the apoptosis of renal cell carcinoma.

AIM: Renal cell carcinoma (RCC), the most frequent type of primary renal malignancies, has a high mortality rate. Serine/threonine kinase 39 (STK39) is associated with various human diseases, including cancers. The current study aimed to investigate the functions of STK39 in RCC. MATERIALS AND METHODS: STK39 expression levels in RCC and paired normal renal tissue samples were detected by real-time polymerase chain reaction and Western blotting analyses. The biological functions of STK39 were explored in two RCC cell lines with STK39 silence. RESULTS: STK39 expression was significantly increased in RCC tissues than in normal renal tissues. Suppression of STK39 expression in ACHN and 786-0 cells significantly suppressed cell proliferation and induced cell apoptosis. Consistently, the expression of PCNA and Bcl-2 was remarkably increased, while the expression of Bax was significantly in STK39 knockdown cells compared to control cells. Furthermore, gene set enrichment analysis identified STK39 as an important regulator of p53 and p38 signaling pathways. STK39 knockdown increased p53 expression and inhibited p38 phosphorylation. Moreover, ectopic expression of STK39 in ACHN cells resulted in a reduced p53 expression and increased c-Myc and p-p38 expression. Such effects were suppressed by p38 inhibitor (SB203580). CONCLUSION: STK39 may exert its oncogenic function in RCC through p38 signaling. Our data suggest that STK39 may represent a potential therapeutic target against RCC.

STK39, overexpressed in osteosarcoma, regulates osteosarcoma cell invasion and proliferation.

Serine/threonine kinase 39 (STK39) is associated with hypertension, autism, Parkinson's disease and various types of cancer in recent years. This study investigated STK39 expression and possible roles in osteosarcoma using qPCR and western blot analysis. Compared to normal bone tissues, the mRNA and protein expression of STK39 was found to be upregulated in osteosarcoma. Using small interfering RNA transfection, STK39 was knocked down into two cell lines of osteosarcoma, U2OS and MG63, and the effects exerted on cell functioning were examined. The results showed that STK39 downregulation inhibited ostesarcoma cell proliferation and invasion. Moreover, STK39 knockdown in osteosarcoma cells significantly affected the expression of proteins connected to cell proliferation (proliferating cell nuclear antigen and p21) and invasion [Twist1, matrix metalloproteinase (MMP)2 and MMP9]. Phosphorylation of Smad2/3 was reduced by STK39 knock down. In conclusion, our data provide evidence that STK39 was overexpressed in osteosarcoma. STK39 may serve as an oncogene by adjusting the proliferation and invasion of osteosarcoma cells.

Role of high expression levels of STK39 in the growth, migration and invasion of non-small cell type lung cancer cells.

Non-small cell type lung cancer (NSCLC) is the most common malignancy and the leading cause of cancer related mortality. In this study, serine/threonine kinase 39 (STK39) was identified as an up-regulated gene in NSCLC tissues by next-generation RNA sequencing. Although STK39 gene polymorphisms may be prognostic of overall survival in patients with early stage NSCLC, the roles of STK39 in NSCLC cancer are poorly understood. In the current study, Genome Set Enrichment Analysis (GSEA) on the RNA-seq data of NSCLC specimens indicated that cancer-related process and pathways, including metastasis, cell cycle, apoptosis and p38 pathway, were significantly correlated with STK39 expression. STK39 expression was significantly increased in NSCLC cases and its protein expression was positively correlated with the poor tumor stage, large tumor size, advanced lymphnode metastasis and poor prognosis. Down-regulation of STK39 in NSCLC cells significantly decreased cell proliferation by blocking of cell cycle and inducing apoptosis. We also found that STK39 knockdown in NSCLC cells remarkably repressed cell migration and invasion. On the contrary, overexpression of STK39 in NSCLC cells had inverse effects on cell behaviors. Taken together, STK39 acts as a tumor oncogene in NSCLC and can be a potential biomarker of carcinogenesis.