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Silencing of STEAP3 suppresses cervical cancer cell proliferation and migration via JAK/STAT3 signaling pathway

Cancer & Metabolism volume 12, Article number: 40 (2024) Cite this article

Abstract

Background

Six-transmembrane epithelial antigen of prostate 3 (STEAP3), an essential constituent of the STEAP family protein, plays a notable role in promoting cancer proliferation and metastasis. Despite the importance of the STEAP gene family in tumor progression, the function of STEAP3 in cervical cancer (CC) remains unclear.

Materials and methods

The expression of STEAP3 protein in CC tissues and cell lines was identified using immunohistochemistry. The Reduced Representation Bisulfite Sequencing (RRBS) was used to detect global gene DNA methylation in CC tissues and paracancerous tissues. Cell viability, proliferation, migration, and invasion, were evaluated using the Cell Counting Kit-8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU), wound repair assay, and transwell assay, respectively. RNA sequencing was applied to explore STEAP3-related signaling pathways. Western blotting was performed to detect the expression of related proteins, including epithelial-mesenchymal transition (EMT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling markers.

Results

Herein, STEAP3 was strongly expressed in CC tissues and associated with poor prognosis. CC samples exhibited lower levels of STEAP3 methylation than normal samples, and the methylation levels of CpG islands in STEAP3 were association with prognosis. In contrast to control group, STEAP3 knockdown suppressed the proliferation and invasion of CC cells and enhanced sensitivity to oxaliplatin. Silencing of STEAP3 led to reduced N-cadherin and vimentin levels and increased E-cadherin expression. RNA sequencing analysis suggested that STEAP3 mediated the activation of the JAK STAT3 signaling pathway. Additionally, inhibition of STEAP3 decreased the phosphorylation of JAK2 and STAT3. Interestingly, colivelin (a STAT3 activator) modified STEAP3-induced cell proliferation, invasion, and expression of related proteins in the EMT and JAK/STAT3 signaling pathway.

Conclusion

STEAP3 was significantly associated with CC progression mediated via the JAK/STAT3 signaling pathway and may serve as an effective therapeutic target.

Background

Globally, cervical cancer (CC) ranks fourth among all types of carcinomas in females, accounting for approximately 600,000 cancer-related new cases and over 300,000 deaths annually [1]. CC ranks as a highly common cancer and continues to be the second leading cause of cancer-related deaths among individuals aged 20–39 years [2]. Persistent high-risk human papillomavirus infection is a major causative factor in the development of CC [3]. Patients with early-stage or locally invasive CC are mainly treated with surgery, radiotherapy, and chemotherapy, with the five-year overall survival (OS) rate exceeding 85% [4]. However, these modalities are associated with considerable side effects and exert limited efficacy in patients with advanced disease. The prognosis of patients suffering from advanced, recurring, or metastatic CC is bleak, showing a mere 16.5% chance of surviving over five years [5]. Therefore, the treatment of advanced CC, particularly metastatic or recurrent CC, presents a considerable challenge.

In recent years, immunotherapy has afforded remarkable results in the treatment of advanced CC. Considering patients with persistent, recurrent, or metastatic CC, treatment with pembrolizumab markedly extended progression-free survival (PFS) and OS when compared with the placebo [6]. In patients with recurrent CC, cimiprilizumab was found to improve global health status, quality of life, and physical functioning when compared with chemotherapy [7]. Despite the notable outcomes achieved with anti-programmed death-1 (PD-1) therapy in CC, the pooled prevalence of PD ligand 1 (PD-L1) positivity was only 58.1% for CC [8]. Accordingly, identifying more efficacious treatment targets may be vital for enhancing the prognosis of patients with CC.

Iron is involved in several biological processes, and maintaining iron balance is essential for standard body stability and cellular function. An imbalance in iron metabolism has been closely linked to cellular oxidative stress, aging, cardiovascular disease, liver disease, and cancer [9, 10]. As a member of the six-transmembrane epithelial antigen of the prostate (STEAP) family, STEAP3 plays a crucial role in regulating the absorption of iron and copper and comprises a six-transmembrane domain at the COOH-terminal and a cytoplasmic N-terminal oxidoreductase domain [11]. Previous research indicates STEAP3’s presence in the plasma membrane, near the nucleus, and inside vesicular tubular structures [12]. Wang et al. have shown that STEAP3 promotes hepatocellular carcinoma (HCC) cell proliferation through intracellular signaling, upregulation of epiregulin (EREG) expression, and nuclear trafficking [13]. In HCC, matrix rigidity hinders the progression of ferroptosis and antitumor immunity by influencing STEAP3 and PD-L2 expression [14]. Reportedly, STEAP3 expression can predict poor prognosis in ovarian cancer, glioblastoma, triple-negative breast cancer, and clear cell renal cell carcinoma [15, 16]. Steiner’s research demonstrated that STEAP3 expression, facilitated by adenovirus, could successfully suppress prostate cancer growth both in vitro and in vivo through induction of apoptosis. Additionally, the researchers discovered that STEAP3 mediated cell apoptosis by promoting caspase-3 activation; in particular, this effect could be blocked by caspase-3 inhibitors Z-DEVD-FMK and Z-VAD-FMK [17]. Zhou et al. have found that the hypoxia-induced lncRNA STEAP3-AS1 shields STEAP3 mRNA against m6A-induced breakdown, thus triggering Wnt signaling pathway that promote the advancement of colorectal cancer [18]. Although the STEAP gene family is vital in the advancement of tumors, the significance of STEAP3 in CC remains uncertain.

The objective of this study is to determine STEAP3’s function in CC. Accordingly, we synthesized data from various public databases and our cohort, revealing a notably elevated level of STEAP3 in CC tissues, which was closely linked to poor prognosis. In addition, DNA methylation analysis and methylation sequencing confirmed that STEAP3 methylation level was significantly reduced in CC tissues. Subsequently, reducing STEAP3 levels hindered cell growth, invasion, epithelial-mesenchymal transition (EMT), and oxaliplatin resistance in CC. Derived from the findings of functional enrichment analysis, STEAP3 enhances CC proliferation and invasion by activating the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Subsequently, cells were treated with colivelin (a STAT3 agonist) and WP1066 (a JAK2/STAT3 inhibitor) to explore the function of the JAK/STAT3 pathway in the advancement of CC. Additionally, Our research also delved into the connection between STEAP3 level and the infiltration of the immune cells and checkpoints, as well as the responsiveness to targeted treatment. These findings indicate that STEAP3 is a potential target in advanced CC patients.

Materials and methods

Data collection

The Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov/) and Genotype-Tissue Expression databases (GTEx; http://gtexportal.org/) provided gene expression data and clinical details for 304 CC and 13 normal samples. GSE7803, comprising 21 CC samples and 10 normal cervical tissue specimens, was acquired from the Gene Expression Omnibus database (GEO; https://www.ncbi.nlm.nih.gov/geo/). The Gene Expression database of Normal and Tumor tissues (GENT2; http://gent2.appex.kr/gent2/) included 114 CC samples and 11 normal samples.

Between 2010 and 2022, the First Affiliated Hospital of Shihezi University collected 111 CC and 29 regular cervical tissue specimens. Prior to specimen collection, no patient had undergone immunotherapy, radiotherapy, or chemotherapy. All patients provided comprehensive clinical and prognostic data. This study was approved by the Ethics Committee of the First Affiliated Hospital of Shihezi University (KJX2022-049-01).

Immunohistochemistry (IHC)

Initially, tissue sections embedded in paraffin were subjected to a triple dewaxing in xylene, each lasting 5 min, followed by rehydration using a series of alcohol concentrations. To retrieve antigens, the samples were heated in a sodium citrate solution for 8 min. Subsequently, the sections underwent a 10-min incubation in 3% hydrogen peroxide shielded from light to obstruct innate peroxidase activity and indiscriminate binding locations. Next, tissue sections were incubated overnight at 4℃ with anti-STEAP3 polyclonal antibody (1:200, PA5-102321; Invitrogen). Sections of tissue underwent a 30-min incubation at 37°C with biotin-tagged anti-rabbit secondary antibodies. Finally, a chromogenic solution of 3,3’-diaminobenzidine (DAB) was applied for 3-min to achieve visualization, with counterstaining performed by applying hematoxylin for 30 s. To calculate the IHC score, the scores for staining intensity (no staining = 0, light brown = 1, brown = 2, and dark brown = 3) and area stained (< 5% = 0, 6–25% = 1, 26–50% = 2, 51–75% = 3, and > 75% = 4) were multiplied. The guidelines were as follows: a score of 4 or lower was classified as mildly positive, whereas a score of 4 or lower was deemed highly positive.

DNA methylation analysis

The relative levels of STEAP3 promoter methylation between CC and normal tissue samples were compared using The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN; https://ualcan.path.uab.edu/). DNA methylation at the STEAP3 gene’s cytosine-guanine (CpG) sites was examined in CC data using MethSurv (https://biit.cs.ut.ee/methsurv/). Additionally, the predictive significance of the CpG methylation in STEAP3 was assessed in CC specimens. Moreover, the link between the methylation status of CpGs in STEAP3 and the OS of patients with CC was assessed.

Reduced representation bisulfite sequencing (RRBS)

DNA from CC tissues and paracancerous tissues was extracted using the QIAamp Fast DNA Tissue Kit (Qiagen, Dusseldorf, Germany). The fragmented DNA samples by using MspI were subjected to bisulfite conversion. DNA adapter-linked DNA was treated with disulphite by using the EZ-DNA Methylation Gold Kit (Zymo Research, CA, USA). After obtaining a sufficient pool of RRBS libraries for sequencing, comprehensive sequencing was performed on the illumina HiSeq 4000 platform (LC Sciences, Hangzhou, China).

Cell culture and transfection

HeLa and SiHa human CC cell lines, acquired from the Shanghai Cell Bank of the Chinese Academy of Sciences, were cultured in high-glucose Dulbecco’s modified Eagle medium (DMEM; Gibco, USA) supplemented with 10% fetal bovine serum (FBS; Omni International, USA) and 1% penicillin and streptomycin. Cells were incubated at 37℃ under 5% CO2 and 95% air.

Short hairpin RNA (shRNAs) targeting STEAP3 (shSTEAP3) and nontargeting shRNAs (shNC) were obtained from GenePharma (Shanghai, China). Target sequences of shRNAs for STEAP3 are listed in Table S1. The insertion of shRNAs into CC cell lines was facilitated by lentiviral infection. Subsequently, infected cells were selected to 2–3 times using puromycin (1.0 µg/mL) to establish stably transfected cell lines.

Western blotting

The extraction of protein samples was performed with a cold RIPA solution, enhanced by a combination of various protease inhibitors. Equal amounts of protein lysate were injected into the wells, subjected to 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and transferred onto polyvinylidene fluoride (PVDF) membranes. Subsequently, the membranes underwent blocking using 5% bovine serum albumin for two hours, followed by an overnight incubation at 4 °C. Next, the PVDF membranes underwent a 2-hour incubation at ambient temperature using horseradish peroxidase-conjugated antibodies (1:5000, ZSGB). Finally, the membranes were visualized using an enhanced chemiluminescence kit, followed by the analysis of protein intensities using ImageJ2 software. TableS2 lists the antibodies used for the western blotting.

Cell proliferation assay

The cell proliferation capacity was assessed through the application of the cell count kit-8 (CCK8) and 5-ethynyl-2’-deoxyuridine (EdU). In the CCK8 experiment, cells were transfected with shRNAs or exposed to colivelin were distributed into 96-well plates, maintaining a density of 103 cells per well. The survival of cells was detected at 24-hour intervals over 5 days. Subsequently, each well was supplemented with10 µL CCK8 solution, and then incubated for another 3 hours at 37 °C. Optical density (OD) readings were taken with a microplate reader at a 450 nm wavelength. In the EdU test, every well in 96-well plates was inoculated with a concentration of 104 cells of STEAP3 knocked-down or colivelin-treated cells. EdU staining was performed according to the manufacturer’s instructions. For EdU quantification, the proportion of EdU + cells to the overall count of Hoechst 33342 + cells was calculated in a given microscopic field.

Transwell assay

Assays for migration and invasion were conducted utilizing transwell chambers (Corning, NY, USA). Briefly, 104 cells in serum-free medium were introduced into the upper chamber, while DMEM (20% FBS) was loaded into the lower chamber. In the experiment involving cell migration, the matrigel matrix was omitted, whereas it was incorporated into the cell invasion experiment. After a 24-hour cultivation phase, the invasive cells underwent fixation with 4% paraformaldehyde and were then colored using crystal violet.

Wound repair assay

Concisely, around 5 × 105 cells were plated in every well of 6-well plates. Upon reaching 100% cell confluency, a sterile tip of 200 µL was employed to etch a wound on the adherent cell monolayers. After 24 hours, wound closure was monitored, and photomicrographs of cell migration were obtained using an Olympus microscope.

RNA sequencing and data analysis

Total RNA was extracted from HeLa cells transfected with shSTEAP3 and shNC. Quantity and purity of RNA were measured using the Bioanalyzer 2100 and RNA 6000 Nano LabChip Kit (Agilent, CA, USA), and all samples with RIN number > 7.0 were allowed to construct sequencing library. The cDNA library was constructed by fragmentation and reverse transcription of purified high-quality RNA, and then was sequenced run with Illumina Novaseq platform (LC-Bio Technology CO., Hangzhou, China). Differential expression of genes was analyzed using edgeR package between two groups. Differentially expressed genes (DEGs) defined as those with false discovery rate (FDR) < 0.05 and the absolute fold change (FC) ≥ 2. DEGs were then subjected to enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways.

Drug resistance assay

In the drug resistance assay, CC cells received escalating concentrations of oxaliplatin (0, 1, 2, 4, 8, 16, 32, 64, or 128 µM) over a 24-hour period. Moreover, the cells were treated with a steady oxaliplatin concentration (10 µM) for 24–48 hours. Cell viability was assessed through the CCK8 assay.

Statistical analyses

Student’s t-test was used to assess mean differences between any two groups. Chi-square and Mann-Whitney U tests were used to examine the link between STEAP3 IHC scores and clinical features. Survival analysis was conducted using the KM method. A correlation test was performed using the Spearman correlation analysis. Statistical analyses were performed using GraphPad Prism (version 8.0) and the R software (version 4.2.1). Statistical significance was set at p < 0.05.

Results

STEAP3 was overexpressed and correlated with unfavorable outcomes in CC

In the TCGA, GSE7803, and GENT2 datasets, there was a notable increase in STEAP3 expression in CC tissues relative to normal tissues. (Fig. 1a). In our cohort, IHC was utilized to measure the protein expression in 111 CC specimens and 29 normal cervical samples (Fig. 1b, c). STEAP3 protein was remarkably upregulated in cervical adenocarcinoma and squamous cell carcinoma tissues. Moreover, strong STEAP3 positivity was observed in a higher number of CC samples (58.6%) than that in normal samples (10.3%). The focus of our research was on the association between STEAP3 protein levels and various clinicopathological features. Table 1 presents the significant correlation between STEAP3 expression and factors such as stage, lymphovascular space invasion (LVSI), and lymph node metastasis (LNM).

Fig. 1
figure 1

STEAP3 was over-expressed and correlated with poor prognosis in CC. (a) The STEAP3 expression in TCGA, GSE7803 and GENT2 databases. (b) Representative images of IHC staining of STEAP3 protein in normal cervical squamous or glandular epithelium and squamous cell carcinoma or adenocarcinoma. (c) The differences of STEAP3 relative protein level between CC and normal cervical tissues in our cohort. (d) Relationship of STEAP3 expression and overall survival and progression free survival in Kaplan-Meier plotter database. (e) Survival analysis of STEAP3 expression related to overall survival and progression free survival from our cohort

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Table 1 The relationship between STEAP3 protein expression and clinical characteristics in cervical cancer
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The results of the KM plot indicated a positive correlation between STEAP3 level and short PFS (hazard ratio [HR] = 3.16, p = 0.015). However, there was no correlation found between STEAP3 expression and OS (HR = 1.6, p = 0.069) of patients, as shown in Fig. 1d. In our CC cohort, survival analysis revealed that individuals with elevated STEAP3 expression had poorer OS (HR = 6.179, p < 0.001) and PFS (HR = 6.525, p < 0.001) (Fig. 1e). According to both univariate and multivariate Cox analyses, STEAP3 expression and cancer stage independently contributed to OS (Table 2) and PFS (Table 3) in patients with CC. Thus, these findings demonstrate that STEAP3 was positively linked to lower survival rates in patients with CC.

Table 2 The univariate and multivariate Cox analysis for overall survival in cervical cancer
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Table 3 The univariate and multivariate Cox analysis for progression free survival in cervical cancer
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Promoter methylation and the role of STEAP3 in CC prognosis

Abnormal DNA methylation is pivotal for tumor development and progression. Hypermethylation frequently drives gene silencing [19]. Our investigation revealed a relationship between STEAP3 promoter methylation and mRNA expression. The Fig. S1a showed the difference of beta values of all CpG probes in STEAP3 located below 1500 bp upstream of transcription start site (TSS) [TSS200, TSS1500]. The result demonstrated that normal cervical tissues exhibited higher levels of STEAP3 methylation than CC samples. To further verified whether STEAP3 DNA methylation inhibited gene expression, we performed RRBS on three pairs of CC tissues and paracancerous tissues. The results confirmed that methylation levels of STEAP3 were significantly lower in CC than in normal adjacent tissue (Fig S1b). Methylation phenotypes of CpG islands in many tumors correlate with patient survival variants [20]. Furthermore, the prognosis and the DNA methylation level at CpG sites in STEAP3 were analyzed using MethSuv in CC. We observed that 12 CpG islands exhibited relatively elevated levels of DNA methylation in CC, including cg21855041, cg05492803, cg13431009, cg00590251, cg00367488, cg00327263, cg20969643, cg00434885, cg10189362, cg26888222, cg16063474 and cg19911116 (Fig. S1c). Then, based on the methylation levels of CpG islands, the best splitting options were selected to divide CC patients into two groups, and Kaplan-Meier survival analysis revealed the correlation between 24 CpG sites and prognosis (Table S3). The findings indicated that six CpG sites were the risk factors (HR > 1) for CC patients, including cg00434885, cg10189362, cg18643762, cg05270572, cg23164999 and cg26888222, could substantially predict poor prognosis. The methylation levels of four CpG islands predicted improved survival rates of patients with CC, including cg25845374, cg16063474, cg21855041 and cg06872331. In addition, methylation levels of the other 14 CpG islands were not statistically associated with prognosis in CC. The forest plot showed that ten CpG sites were significantly associated with overall survival of CC patients (Fig. S1d). The findings suggested that DNA methylation contributes to the STEAP3 expression in CC.

STEAP3 knockdown suppressed proliferation, migration, and invasion of CC cells

To further investigate the role of STEAP3 in CC tumor advancement, two CC cell lines with a stable STEAP3 knockdown were established by transfecting STEAP3 shRNA. The effect of shRNA on STEAP3 expression was assessed through western blotting. Based on our findings, shSTEAP3#3 elicited the greatest knockdown effect (Fig. 2a). Accordingly, cell viability was significantly inhibited in STEAP3-silenced CC cells in contrast to shNC-infected cells (Fig. 2b). According to the EdU assay results, STEAP3 knockdown reduced the proliferation rates of HeLa and SiHa cells (Fig. 2c).

Fig. 2
figure 2

STEAP3 promoted CC cell proliferation. (a) Detection of STEAP3 protein expression in STEAP3-knockdown and negative control CC cells lines (HeLa and SiHa) by western blot. (b) Cell viability analysis for HeLa and SiHa cells with or without STEAP3 silence using CCK8 assay. (c) Representative images of EdU assay for STEAP3-silenced CC cells. Scale bar indicates 100 μm. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001

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Meanwhile, STEAP3-downregulated HeLa and SiHa cells exhibited poor capacity for migration and invasion (Fig. 3a). Furthermore, an assay for wound healing was conducted to evaluate the differences in migration speed between the shNC and STEAP3 knockdown groups (Fig. 3b). These findings indicated that STEAP3 silencing suppressed the migration of CC cells. Furthermore, western blotting was performed to identify markers associated with EMT, such as E-cadherin, N-cadherin, and vimentin. As shown in Fig. 3c, decreased STEAP3 expression reduced the levels of N-cadherin and vimentin proteins in HeLa and SiHa cells. Nonetheless, E-cadherin protein expression was markedly improved in shSTEAP3 CC cell lines when contrasted with that in the shNC groups. Overall, the results indicate a crucial function of STEAP3 in proliferation, migration, and invasion of CC.

Fig. 3
figure 3

Knockdown of STEAP3 inhibited CC cells migration and invasion. (a) Representative photos of trasnwell assay for evaluating the effects on the migration and invasion of HeLa and SiHa cells after STEAP3 knockdown. (b) Comparison of cell migration ability between STEAP3 knockdown and negative control CC cells by wound healing assay. (c) EMT-related protein levels in HeLa and SiHa cells transfected with shSTEAP3. Scale bar indicates 100 μm. ns, not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001

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STEAP3 regulated the JAK/STAT3 pathway in CC cell lines

To further explore the potential mechanisms by which STEAP3 regulates cervical cancer proliferation and metastasis, we used the RNA sequencing method to profile gene expression changes that occur in response to STEAP3 knockdown. In HeLa cells transfected with shSTEAP3, 151 genes were up-regulated and 91 genes were down-regulated by over 2-fold, compared with control cells (Fig. S2a, Table S4). Next, we performed KEGG enrichment analysis to explore the biological functions of these genes (Table S5). The results suggested an enrichment of pathway terms associated with immunity like NOD-like receptor signaling pathway, and metabolism like fatty acid degradation, where the pathway associated with tumor progression was mainly cAMP signaling pathway and JAK STAT signaling pathway (Fig. 4a). There are strong evidences that the JAK/STAT pathway played an important role in the proliferation and metastasis of CC [21, 22]. One study showed that si-ITGB6 restrained CC cell proliferation, migration and invasion through suppressing the phosphorylation of JAK1, JAK2 and STAT3 [21]. The human papillomavirus E6/E7 proteins induced growth and migration of CC cells by activating JAK/STAT signaling cascade [22]. Western blot analysis confirmed that STEAP3 knockdown markedly suppressed the phosphorylation of JAK2 (p-JAK2) and STAT3 (p-STAT3), but had no effect on the expression of total JAK2 and STAT3 proteins in HeLa and SiHa cells (Fig. 4b). The results indicated that silencing of STEAP3 inhibited JAK2 protein activation and receptor tyrosine phosphorylation (Y1007) in CC cells, resulting in blocked STAT3 docking site formation in the cytoplasm. The serine phosphorylation of the STAT3 protein (S727) was suppressed because of reduced tyrosine phosphorylation [23]. The formation of activated p-STAT3 homo- or heterodimers was blocked through the interactions of intermolecular SH2-phosphotyrosine, leading to a reduction of STAT3 dimerization into the nucleus to bind to DNA, with the end result that transcription is inhibited [24]. Moreover, we examined whether the suppressive impacts of STEAP3 were facilitated through the JAK/STAT3 pathway. Following the treatment of HeLa and SiHa cells with colivelin, we found that colivelin enhanced the protein levels of vimentin, N-cadherin, p-JAK2, and p-STAT3 but reduced E-cadherin expression in CC cell lines and reversed the expression of these proteins triggered by STEAP3 downregulation (Fig. 4c). In addition, WP1066 led to a reduction in STAT3 and JAK2 phosphorylation, reduced the expression of vimentin and N-cadherin proteins, and enhanced E-cadherin level in CC cell lines (Fig. S2b, c). Therefore, the inhibitory effect of STEAP3 knockdown on EMT in CC may be mediated via the JAK/STAT3 axis.

Fig. 4
figure 4

STEAP3 regulated JAK2/STAT3 singling pathway in CC cell lines. (a) Top 20 enrichment pathways of KEGG. (b) Western blot for protein relative expression of total and phosphorylated JAK2 and STAT3 in HeLa and SiHa cells transfected with STEAP3-silenced and negative control shRNA. (c) Comparison of the related protein expression involved in JAK2/STAT3 pathway and EMT among HeLa and SiHa cells with STEAP3 knockdown and colivelin exposure by western blot. ns, not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001

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Colivelin counteracted the inhibition of cell proliferation, migration, and invasion

We explored the potential significance of the JAK/STAT3 pathway in STEAP3-mediated CC tumorigenesis using rescue assays. We found that the colivelin significantly abrogated STEAP3 knockdown and suppressed the growth of HeLa and SiHa cells, as evidenced in the CCK8 and EdU assays (Fig. 5a, b). Moreover, treatment with colivelin partially abolished decreased invasion and migration of CC cells resulting from the suppression of STEAP3. (Fig. 5c). Together, these results implied that the oncogenic impact of STEAP3 on CC was mediated via the JAK/STAT3 pathway.

Fig. 5
figure 5

Colivelin abolished the inhibition of CC cells proliferation, migration and invasion. (a) Cell vitality for negative control and STEAP3-silenced HeLa and SiHa cells treated with colivelin by CCK8 assay. (b) Representative photos of cell proliferation of HeLa and SiHa cells among groups using EdU assay in rescue experiment. (c) Representative photos of migration and invasion by transwell assay in HeLa and SiHa cells with STEAP3 knockdown and colivelin. Scale bar indicates 100 μm. ns, not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001; **** p < 0.0001

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Suppressing STEAP3 reduced oxaliplatin resistance in CC cells

Platinum drugs, including cisplatin, carboplatin, oxaliplatin, and paclitaxel, have been extensively used in the management of gynecologic tumors (especially ovarian and cervical cancers) [25, 26]. However, chemoresistance and cytotoxicity of platinating agents greatly hinder their clinical applications [27]. To explore the potential clinical significance of STEAP3, various concentrations of oxaliplatin were administered to CC cells over a 24-hour period. The CCK8 assay results revealed that STEAP3 silencing sensitized CC cells to oxaliplatin (Fig. S3a). Cell viability was evaluated through the CCK8 assay following a 24 or 48-hour period of consistent oxaliplatin exposure. (Fig. S3b). Both HeLa and SiHa cells with STEAP2 knockdown were significantly more sensitive to 10 µM oxaliplatin than the negative control group. Collectively, these findings demonstrated that downregulated STEAP3 expression could induce apoptosis and reduce chemoresistance to oxaliplatin in CC cell lines.

Discussion

Elevated STEAP3 levels have been linked to tumor advancement and are indicative of poor outcomes in several human cancers [16]. However, the molecular processes that contribute to its cancer-inducing functions remain largely unknown. Our current study noted an unusual elevation in STEAP3 level in CC tissues relative to normal tissues, correlating positively with stage, LNM, and LVSI, and reduced OS and PFS. Using various in vitro assays, we demonstrated that STEAP3 expression markedly improved CC cell growth and migration through the activation of JAK-STAT3 signaling axis. The above findings robustly endorse STEAP3’s carcinogenic ability of STEAP3 in the advancement of CC. Importantly, STEAP3 could potentially act as a standalone predictive indicator for the survival of patients with CC.

DNA methylation is characterized by the covalent bonding of a methyl group at the cytosine 5-carbon position of genomic CpG dinucleotides and is recognized as a key epigenetic modification for controlling gene expression [28]. Growing evidence indicates a link between changes in DNA methylation patterns and a series of age-associated diseases, including vascular disease, Alzheimer’s disease, and cancer [29]. DNA methylation patterns may could be significantly influential in the formation and advancement of tumors via the regulation of oncogenes and tumor-inhibiting gene expression [30]. Based on the IHC results of our cohort and analysis of TCGA datasets, patients with CC had notably elevated levels of STEAP3 mRNA and protein. Currently, the processes underlying increased STEAP3 expression in CC remain largely elusive. Our research revealed that STEAP3 DNA methylation in CC was markedly reduced when compared with that observed in normal samples, and a significant correlation was detected between the methylation of various CpG sites and CC survival, thereby suggesting that diminished STEAP3 promoter methylation can lead to enhanced STEAP3 expression in CC.

Malignant tumors share common biological behaviors, including metastasis and invasion, form the pathological foundation of their recurrence and progression. High STEAP3 expression has been shown to enhance migration and invasion abilities and predict a negative outcome in gliomas [31]. In clear cell renal cell carcinoma, STEAP3 could be a predictive biomarker, promoting EMT by downregulating CDH1 [32]. In HCC, STEAP3 was found to promote cancer cell growth by improving stem cell characteristics and advancing the cell cycle through RAC1-ERK-STAT3 and RAC1-JNK-STAT6 signaling [13]. Moreover, it is possible that STEAP3 plays a role in the processes of apoptosis and the cell cycle [17, 18]. Reportedly, STEAP3 expression was increased via p53 activation and played a role in facilitating apoptosis and delaying the cell cycle by interacting with Myt1 and Nix [33, 34].

Furthermore, advanced cervical cancer is characterized by extensive metastasis and invasion. However, the unique regulatory function and mechanism of STEAP3 in CC are still not well understood. Herein, we also investigated the effect of STEAP3 on various biological functions. Downregulated STEAP3 expression hindered the proliferation, migration, and invasion of HeLa and SiHa cells. Irregular EMT initiation is crucial for tumor metastasis and invasion. Accordingly, changes in EMT-associated proteins were examined. Notably, shSTEAP3 reduced expression levels of N-cadherin and vimentin while increasing E-cadherin level in CC. The initial findings indicated that STEAP3 might be a significant factor contributing to CC deterioration.

The JAK/STAT pathway is a cytokine-stimulated signal transduction pathway activated by multiple cytokines or growth factors and consists of the tyrosine kinase receptor JAK and STAT families [35]. The activation or deactivation of JAK/STAT signaling is linked to the occurrence of multiple cancers, including CC, and is crucial for the advancement of tumors [36]. JAK2 and STAT3, key proteins in the JAK/STAT3 pathway, get activated in most cancers via tyrosine phosphorylation. GSEA revealed a notable enrichment of the JAK-STAT3 pathway in the group with high STEAP3 expression. Furthermore, STEAP3 expression was positively correlated with JAK2 and STAT3 levels. Silencing of STEAP3 significantly lowered the levels of p-JAK2 and p-STAT3. Colivelin and WP1066 were employed to comprehensively explore the association between STEAP3 expression and the JAK/STAT3 signaling pathway in CC. Treatment with colivelin reversed cell proliferation, invasion, and activation of the JAK/STAT3 axis, as well as EMT-associated proteins triggered by STEAP3.

Cancer chemotherapy can be curative in various tumors by inhibiting tumor cell proliferation and inducing apoptosis [37, 38]. Oxaliplatin, a platinum-based chemotherapy drug, is used to manage recurrent or metastatic CC, and their anticancer effects include promoting DNA damage, halting the cell cycle, and increasing apoptosis [39,40,41]. Nonetheless, CC is linked to a persistently high mortality rate, which is attributed to a diminished responsiveness to chemotherapy drugs or potential drug resistance [42]. Consequently, it is essential to increase tumor cell responsiveness to chemotherapeutic drugs and identify indicators that may predict chemotherapy effectiveness. In the current study, we found that reducing STEAP3 levels increased the responsiveness of HeLa and SiHa cells to oxaliplatin, thereby suggesting that STEAP3 levels can predict the effect of oxaliplatin chemotherapy on CC cells.

Conclusions

In conclusion, our results revealed that STEAP3 expression is positively related to unfavorable outcomes in patients with CC, and STEAP3 silencing suppresses CC cell survival, invasion, and EMT progression by inactivating the JAK/STAT3 pathway. STEAP3 may serve as a promising therapeutic target in patients with advanced cervical cancer.

Data availability

The raw RNA-seq data have been submitted to the NCBI Gene Expression Omnibus (GEO) datasets with accession number (GSE284355).

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Acknowledgements

We would like to thank Editage (www.editage.cn) for English language editing.

Funding

This work is supported by the National Natural Science Foundation of China (82072893, 82360541), the Corps Science and Technology Tackling Program (2023AB055) and the Technological Innovation Leading Talent Program of Tianshan Talent (CZ001201).

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Author notes

  1. Zouyu Zhao, Panpan Yu and Yan Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, First Affiliated Hospital, Shihezi University, Shihezi, China

    Zouyu Zhao, Panpan Yu, Yan Wang, Hong Li, Hui Qiao, Chongfeng Sun, Lina Zhu & Ping Yang

  2. Department of Physiology, School of Medicine, Shihezi University, Shihezi, China

    Panpan Yu

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Contributions

PY and ZZ conceived and supervised the project. HQ, CS, HL, and LZ collected and followed the information of patients. ZZ, PPY, YW performed the experiments. HL prepared the samples for RNA sequencing. ZZ performed the data analyses and wrote the manuscript. PY reviewed and edited the manuscript. All authors approved the final manuscript.

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Correspondence to Ping Yang.

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40170_2024_370_MOESM1_ESM.tif

Supplementary Material 1: Figure S1 Promoter methylation of STEAP3 in CC. (a) The differences of STEAP3 promoter methylation in CC and normal tissues. (b) The DNA methylation level of STEAP3 between CC and paraneoplastic tissues in experiment. (c) The heatmap of DNA methylation for STEAP3. (d) Methylation levels of CpG islands in STEAP3 on the prognosis of patients with CC.

40170_2024_370_MOESM2_ESM.tif

Supplementary Material 2: Figure S2 Correlation of STEAP3 with JAK2/STAT3 pathway. (a) The differentially expressed genes between shSTEAP3 group and shNC group. (b, c) WP1066 inhibited CC cells JAK2/STAT3 pathway and EMT related markers expression. ns, not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001.

40170_2024_370_MOESM3_ESM.tif

Supplementary Material 3: Figure S3 Suppressing STEAP3 reduced oxaliplatin resistance. (a) Cell viability analysis for HeLa and SiHa cells with or without STEAP3 silencing following treatment with an increasing concentration of oxaliplatin for 24 hours by CCK8 assay. (b) Cell viability for knockdown of STEAP3 and negative control CC cells after treatment with the indicated concentration of oxaliplatin for 24 hours and 48 hours. ***, p < 0.001; **** p < 0.0001.

Supplementary Material 4: Figure S4 Blots images.

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Supplementary Material 9

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Zhao, Z., Yu, P., Wang, Y. et al. Silencing of STEAP3 suppresses cervical cancer cell proliferation and migration via JAK/STAT3 signaling pathway. Cancer Metab 12, 40 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40170-024-00370-2

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Keywords

Cancer & Metabolism

ISSN: 2049-3002