Elevated AKIP1 expression is associated with tumor invasion, shorter survival time and decreased chemosensitivity in endometrial carcinoma
- Authors:
- Published online on: June 20, 2022 https://doi.org/10.3892/ol.2022.13388
- Article Number: 268
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Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Endometrial carcinoma, as a common gynecological malignancy, displays increasing incidence rate globally (1,2). An average annual increase of 11.3% for endometrial carcinoma incidence was observed in South Africa between 2003 and 2012, and an increase was also observed in Brazil, America, Japan and other 24 countries/regions (2). Regarding the management of endometrial carcinoma, total hysterectomy and bilateral salpingo-oophorectomy (with or without adjuvant therapy) are recommended for affected patients who are suitable for surgery, while external beam radiation therapy and/or brachytherapy (with or without chemotherapy) is commonly applied for those patients who are not suitable for surgery (3,4). For those patients with endometrial carcinoma who meet the criteria for consideration of fertility-sparing options, hormonal therapy (continuous progestin-based therapy) may be considered as an alternative therapy option (4). Despite the appropriate management, patients with endometrial carcinoma may experience multiple recurrences (locoregional recurrence and extrapelvic recurrence), leading to a poor long-term outcome (5,6). Thus, identifying potential biomarkers to improve the prognosis for patients with endometrial carcinoma is critical and urgent.
A-kinase-interacting protein 1 (AKIP1) has been reported to serve as an oncogene in several solid tumors, especially in gynecological malignancies (7,8). For instance, AKIP1 may promote cervical cancer cell invasion and migration through regulating nuclear factor (NF)-κB-induced epithelial-to-mesenchymal transition (EMT) (7). Moreover, AKIP1 can enhance cervical cancer cell proliferation and angiogenesis by upregulating CXC-chemokines (such as CXCL1, CXCL2 and CXCL8) (8). In the clinical field, AKIP1 has been identified as a potential prognostic biomarker for clear cell renal cell carcinoma, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma and cervical cancer (9–13). To the best of our knowledge, no study has explored the clinical role of AKIP1 in patients with endometrial carcinoma.
The present study collected 101 pairs of tumor tissue and adjacent tissue from patients with endometrial carcinoma in order to explore the associations between AKIP1 expression and clinicopathological features and prognosis. In addition, the present study further assessed the effect of AKIP1 on regulating chemosensitivity in an endometrial carcinoma cell line.
Materials and methods
Patients
The present study retrospectively analyzed the cases of 101 female patients with endometrial carcinoma who were treated by surgical resection at Handan Central Hospital (Handan, China) between January 2016 and January 2020. By reviewing their clinical data, the eligible patients were enrolled based on the following criteria: i) Histopathological diagnosis of endometrial carcinoma; ii) age >18 years; iii) treated by surgical resection; iv) surgically removed specimens, including tumor and tumor-adjacent tissues, were available and accessible; v) main clinical data and survival data were retrievable; and vi) no history of other malignancies before the diagnosis of endometrial carcinoma. Approval was acquired from the Institutional Review Board (IRB) of Handan Central Hospital (approval number, HDZXYY-Ethics-2021015) before the implementation of the study. The requirement for written informed consent was absolved by the IRB, as the study was performed based on post-operative patient samples and existing clinical data, which involved no risk to the patients themselves and did not affect the privacy of the patients.
Data acquisition
The main preoperative clinical features of the patients were obtained from medical records or outpatient records, and included age, menopausal status (pre-menopause or post-menopause), comorbidities [diabetes mellitus (DM) and hypertension], histological subtype (endometrioid carcinoma, serous endometrial carcinoma and clear cell endometrial carcinoma), myometrial invasion status, cervical invasion status, lymphovascular invasion status and International Federation of Gynecology and Obstetrics (FIGO) stage (14). Furthermore, the survival data of the patients was collated from the follow-up documents, and the overall survival (OS) time was determined.
Specimen acquisition
Tumor and tumor-adjacent tissue (2 cm from the tumor tissue) specimens (formalin-fixed using 4% paraformaldehyde for >24 h and paraffin-embedded and sliced into 4-µm sections) of all patients were acquired from the specimen repository in order to perform an immunohistochemistry (IHC) assay aimed at evaluating AKIP1 protein expression. Meanwhile, 54 of the 101 patients had fresh-frozen specimens that were immediately stored in liquid nitrogen following surgical removal (stored at −80°C), which were also collected to determine the mRNA expression levels of AKIP1 by reverse transcription-quantitative PCR (RT-qPCR) assay.
IHC assay
The IHC staining was implemented as described in a previous study (15), with the AKIP1 Monoclonal Antibody as the primary antibody (cat. no. MA5-26998) and Goat anti-Mouse IgG (H+L) as the secondary antibody (cat. no. 31430) (both Invitrogen; Thermo Fisher Scientific, Inc.). The primary antibody was diluted 1:150 and the secondary antibody was diluted 1:20,000. The staining (10 min at room temperature) and counterstaining (5 min at room temperature) were performed using diaminobenzidine and hematoxylin, respectively. The IHC staining result was viewed on a light microscope, and the AKIP1 expression was evaluated using an IHC scoring method (16). In brief, five high-power fields (×200 magnification) were randomly selected in each slide, then the mean percentage of positively stained cells in five fields was calculated and scored as 0 (0%), 1 (1–25%), 2 (26–50%), 3 (51–75%) or 4 (76–100%). Meanwhile, the staining intensity was scored as 0 (negative), 1 (weak), 2 (moderate) or 3 (strong), and the mean staining intensity score of five fields was calculated. The final IHC score was obtained by multiplying the two scores. Using a cut-off score of 3, the AKIP1 protein expression was classified as low expression (IHC score ≤3) and high expression (IHC score >3).
RT-qPCR assay
After extraction of total RNA from the tumor tissues and adjacent tissues using TRIzol® (Invitrogen; Thermo Fisher Scientific, Inc.), RT was conducted using iScript™ Reverse Transcription Supermix (Bio-Rad Laboratories, Inc.) according to the manufacturer's instructions. qPCR was performed using the QuantiNova SYBR Green PCR Kit (Qiagen GmbH). The following thermocycling conditions were applied: 95°C for 2 min, followed by 40 cycles of 95°C for 5 sec and 61°C for 30 sec. The relative expression of AKIP1 was calculated using the 2−ΔΔCq method, where GAPDH served as an internal reference (17). The forward and reserve primers were designed in line with a previous study (11). According to the median expression level in the tumor tissue, the AKIP1 mRNA expression was classified as low expression (up to and including the median level) and high expression (greater than the median level) for survival analysis.
In vitro experiment
Human endometrial carcinoma Ishikawa cells (Shanghai Enzyme Research Biotechnology Co., Ltd.) were cultured in DMEM (Thermo Fisher Scientific, Inc.) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin (both Gibco; Thermo Fisher Scientific, Inc.), in a 5% CO2 atmosphere at 37°C. The small interfering (si)RNA targeting AKIP1 (50 nM) (sense, 5′-GGAGGCAGCTATCAAATATTT-3′ and antisense, 5′-ATATTTGATAGCTGCCTCCTT-3′) and the corresponding negative control (NC) siRNA (50 nM) (sense, 5′-GAATTAATTAAAGATGGCCCGTTGTACT-3′ and antisense, 5′-TCATCGAAGTTATAGGGATACATTACGTGATC-3′) were purchased from Thermo Fisher Scientific, Inc., and separately transfected into the 5×105 Ishikawa cells using Lipofectamine® 3000 reagent (Thermo Fisher Scientific, Inc.) at 37°C for 6 h. At 48 h post-transfection, the AKIP1 mRNA expression levels were detected. Subsequently, the Ishikawa cells were divided into three groups: Cells transfected with AKIP1 siRNA, cells transfected with NC siRNA and cells without transfection (used as a blank control), accordingly. Cisplatin and paclitaxel (both MilliporeSigma; Merck KGaA) were used for the chemosensitivity assay. The cisplatin was prepared at concentrations of 0, 5, 10, 20, 40 and 80 µM, and the paclitaxel was prepared at concentrations of 0, 0.5, 1, 2, 4 and 8 nM, according to previous studies (18–20). The cells in the three groups were respectively treated with the cisplatin and paclitaxel at the prepared concentrations for 48 h at 37°C, and then the cell viability in each group was determined using Cell Counting Kit-8 reagent (Beyotime Institute of Biotechnology) for 2 h and detected at a wavelength of 450 nm.
Statistical analysis
SPSS 26.0 (IBM Corp.) was applied for data analysis, and GraphPad Prism 7.02 (GraphPad Software Inc.) was used for graph plotting. Quantitative data are presented as the mean ± standard deviation or median (interquartile range). Qualitative data are presented as n (%). The comparison of AKIP1 expression between tumor and adjacent tissues was performed using Wilcoxon's signed rank test. Receiver operating characteristic curve analysis was applied to evaluate the accuracy of AKIP1 expression for differentiating between different tissues. Associations between AKIP1 expression and clinical features were analyzed using Spearman's correlation (for ordered categorical variables) and Wilcoxon's rank sum test (for unordered categorical variables). OS was displayed in Kaplan-Meier curves and analyzed by log-rank test. Prognostic implications of variables were estimated using Cox proportional hazard model regression analysis. To further validate the correlation of AKIP1 with OS, a search for AKIP1 was performed in The Human Protein Atlas database (https://www.proteinatlas.org/ENSG00000130707-ASS1/pathology/endometrial+cancer), from which, AKIP1-related survival data derived from The Cancer Genome Atlas database (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga) was obtained. In the in vitro experiment, AKIP1 mRNA expression was compared using one-way analysis of variance followed by Tukey's test. The cell viability between the AKIP1 siRNA group and the NC siRNA group was determined by unpaired t-test. The half maximal inhibitory concentration (IC50) was estimated by Probit regression, and the mean IC50 between the AKIP1 siRNA group and the NC siRNA group was also determined by t-test. The experiments were all performed in triplicate. P<0.05 was used to indicate a statistically significant difference.
Results
Clinical features of patients with endometrial carcinoma
The mean age of the analyzed patients with endometrial carcinoma was 63.5±9.6 years (Table I). There were 15 (14.9%) and 86 (85.1%) patients with a pre-menopause and post-menopause status, respectively. Moreover, 67 (66.3%), 11 (10.9%), 16 (15.8%) and 7 (6.9%) patients were diagnosed with endometrioid carcinoma G1/G2, endometrioid carcinoma G3, serous endometrial carcinoma and clear cell endometrial carcinoma, respectively. Furthermore, 61 (60.4%), 14 (13.9%), 20 (19.8%) and 6 (5.9%) patients were graded as FIGO stage I, stage II, stage III and stage IV, respectively. The detailed clinical characteristics of the patients with endometrial carcinoma are listed in Table I.
AKIP1 expression in patients with endometrial carcinoma
AKIP1 IHC score was increased in tumor tissue compared with that in adjacent tissue in the patients with endometrial carcinoma [median (IQR), 4.0 (3.0-6.0) vs. 2.0 (2.0-4.0); P<0.001; Fig. 1A and B]. Moreover, AKIP1 IHC score was able to differentiate tumor tissue from adjacent tissue, with an area under the curve (AUC) of 0.778 (95% CI, 0.715-0.842; Fig. 1C).
AKIP1 mRNA expression was also elevated in tumor tissues compared with that in adjacent tissues in the patients with endometrial carcinoma [median (IQR), 2.219 (1.739-3.489) vs. 0.993 (0.719-1.577); P<0.001; Fig. 1D]. Moreover, AKIP1 mRNA expression was also able to differentiate between tumor tissue and adjacent tissue, with an AUC of 0.865 (95% CI, 0.797-0.932; Fig. 1E).
Association between tumor AKIP1 expression and clinical features in patients with endometrial carcinoma
Even though AKIP1 IHC score was not associated with myometrial invasion ≥1/2 (P=0.084; Fig. 2A) or cervical stroma invasion (P=0.141; Fig. 2B), increased AKIP1 IHC score was associated with lymphovascular invasion (P=0.007; Fig. 2C) and advanced FIGO stage (P=0.002; Fig. 2D) in the patients with endometrial carcinoma.
Although there was no association between AKIP1 mRNA expression and myometrial invasion ≥1/2 (P=0.238; Fig. 2E) or cervical invasion (P=0.297; Fig. 2F), elevated AKIP1 mRNA level was associated with lymphovascular invasion (P=0.020; Fig. 2G) and higher FIGO stage (P=0.027; Fig. 2H) in the patients with endometrial carcinoma.
Association between tumor AKIP1 expression and OS in patients with endometrial carcinoma
High AKIP1 protein expression (defined as an IHC score >3) was associated with a shorter accumulating OS time in the patients with endometrial carcinoma (P=0.035; Fig. 3A). However, high AKIP1 mRNA expression (defined as expression >2.219) was not associated with OS time (P=0.145; Fig. 3B). Further validation using The Cancer Genome Atlas database showed that high AKIP1 mRNA expression appeared to be associated with shorter OS time in the patients with endometrial carcinoma, although no statistical significance was found (P=0.052; Fig. S1).
Independent factors for OS in patients with endometrial carcinoma
Univariate Cox regression analysis identified that tumor AKIP1 protein expression (high vs. low) [hazard ratio (HR), 3.622; 95% confidence interval (CI), 1.013-12.946; P=0.048], cervical invasion (stromal vs. none or epithelial) (HR, 3.821; 95% CI, 1.382-10.565; P=0.010), lymphovascular invasion (yes vs. no) (HR, 3.769; 95% CI, 1.363-10.419; P=0.011) and higher FIGO stage (HR, 2.170; 95% CI, 1.382-3.406; P=0.001) were all associated with decreased OS time in the patients with endometrial carcinoma (Table II). Further multivariate Cox regression analysis found that tumor AKIP1 protein expression (high vs. low) (HR, 3.910; 95% CI, 1.095-13.965; P=0.036) and cervical invasion (stromal vs. none or epithelial) (HR, 4.104; 95% CI, 1.483-11.360; P=0.007) were independently associated with shorter OS time.
Effect of AKIP1 knockdown on chemosensitivity
Silencing of AKIP1 decreased the mRNA expression levels of AKIP1 in Ishikawa cells (P=0.002; Fig. S2), indicating successful transfection. Moreover, silencing of AKIP1 significantly decreased the relative cell viability of Ishikawa cells under treatment with 5 µM (P=0.015), 10 µM (P=0.045), 20 µM (P=0.018) and 40 µM (P=0.049) cisplatin compared with the NC siRNA group (Fig. 4A). However, silencing of AKIP1 only significantly decreased the relative cell viability of the Ishikawa cells under treatment with 4 nM paclitaxel (P=0.026), but not at other concentrations (all P>0.05) compared with the NC siRNA group (Fig. 4B). Furthermore, AKIP1 siRNA reduced the IC50 of paclitaxel and cisplatin (Fig. 4C and D).
Discussion
AKIP1 has been identified as a new and potential biomarker in several types of cancer in the clinical field (9–12). Previous studies have indicated that AKIP1 expression is upregulated in tumor tissue compared with that in non-cancerous adjacent tissue in patients with clear cell renal cell carcinoma, non-small cell lung cancer, colorectal cancer and hepatocellular carcinoma (9–12); however, to the best of our knowledge, there are no studies on the clinical value of AKIP1 in patients with endometrial carcinoma. Furthermore, most studies have detected AKIP1 protein expression by evaluating the IHC score from surgical specimens, while the mRNA expression levels of AKIP1 in these specimens have not been determined. Therefore, in the present study, tumor tissues and adjacent tissues were collected from patients with endometrial carcinoma in order to detect AKIP1 protein levels by IHC assay and AKIP1 mRNA expression levels by RT-qPCR, and to further explore the clinical value of AKIP1 in patients with endometrial carcinoma. An increase in AKIP1 expression was observed in the tumor tissues compared with that in the adjacent tissues, which other studies have suggested may be due to AKIP1 promoting angiogenesis through the regulation of the NF-κB and AKT pathways. This would lead to enhanced blood vessel formation, which is one of the hallmarks of endometrial carcinoma (8,21,22).
In terms of the association between AKIP1 expression and clinical features in patients with cancer, high AKIP1 expression has been reported to be associated with advanced TNM stage in clear cell renal carcinoma, non-small cell lung cancer and colorectal carcinoma (9–11). Moreover, high AKIP1 expression is also correlated with poor pathological differentiation and lymph node metastasis in patients with non-small cell lung cancer (11). In the present study, increased AKIP1 expression was associated with tumor invasion and advanced FIGO grade in the patients with endometrial carcinoma. The following reasons, suggested by other studies, could be applied to explain these findings: i) AKIP1 promotes EMT, which further enhances cancer invasion and metastasis by regulating the PI3K/Akt pathway, as well as mediating the expression of transcription factor zinc finger E-box binding homeobox 1 promoter and Slug, which thereby leads to the presence of tumor invasion in patients with endometrial carcinoma (7,23,24). ii) Occurrence of lymphovascular invasion, myometrial invasion ≥1/2 and cervical stroma invasion are associated with advanced FIGO grade in patients with endometrial carcinoma (25,26). Therefore, elevated AKIP1 expression is associated with advanced FIGO stage in patients with endometrial carcinoma.
The association between AKIP1 and prognosis in patients with cancer is also noteworthy. For example, high AKIP1 protein expression has been shown to be associated with early recurrence (defined as recurrence within 2 years) and is independently correlated with shorter recurrence-free survival times in patients with hepatocellular carcinoma (12). Moreover, high AKIP1 expression is an independent factor for shorter OS time in patients with clear cell renal carcinoma, non-small cell lung cancer and colorectal carcinoma (9–11). In the present study, high tumor AKIP1 protein expression was independently associated with decreased OS time in the patients with endometrial carcinoma. Possible reasons to explain these findings, as suggested by previous studies, were: i) Elevated tumor AKIP1 expression promoting endometrial carcinoma cell invasion and migration through the mediation of multiple pathways (such as the Akt/GSK-3β and PI3K/Akt pathways), thus leading to an enhanced risk of tumor recurrence and an unfavorable prognosis in patients with endometrial carcinoma (7,27,28). ii) As illustrated in the present in vitro study, silencing of AKIP1 enhanced the chemosensitivity to cisplatin and paclitaxel in an endometrial carcinoma cell line, thus its overexpression may decrease the postoperative chemosensitivity, thereby leading to an unfavorable prognosis in patients with endometrial carcinoma.
Resistance to chemotherapy drugs is another factor contributing to an unfavorable prognosis in patients with endometrial carcinoma (29). A previous study indicated that overexpression of AKIP1 promoted the resistance to temozolomide by regulating CXCL1- and CXCL8-mediated NF-κB and AKT pathways in glioblastoma cells (30). Moreover, AKIP1 was shown to be associated with chemotherapy resistance in ovarian cancer using transcriptomic data (31). However, to the best of our knowledge, no relevant study has investigated the effect of AKIP1 on chemosensitivity in endometrial carcinoma. In the present study, it was shown that silencing of AKIP1 could enhance the chemosensitivity to cisplatin and paclitaxel (to some extent) in endometrial carcinoma cells, which may be explained by the silencing of AKIP1 regulating multiple chemosensitivity-related signaling pathways (such as NF-κB and AKT pathways) to enhance cisplatin and paclitaxel chemosensitivity in endometrial carcinoma (30,32,33). The present findings suggested that AKIP1 was involved in regulating the chemosensitivity of the endometrial carcinoma cell line, which provided some evidence for further therapeutic intervention.
The present study has several limitations. For instance, the sample size was relatively small; therefore, further studies with a larger sample size are needed to validate the clinical value of AKIP1 in patients with endometrial carcinoma. Furthermore, most patients in the current study did not live in the local region and they did not receive long-term routine management/follow-up after surgery in the same hospital; therefore, the present study did not evaluate the disease relapse information of the patients. Furthermore, the present study did not detect the detailed molecular mechanism of AKIP1 with regard to its regulation of chemosensitivity in endometrial carcinoma, which could be explored in future studies.
In conclusion, the present study indicated that elevated AKIP1 expression was associated with tumor invasion, shorter survival times and reduced chemosensitivity in patients with endometrial carcinoma.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
FZ conceived and designed the study. ALL, TYZ, ZLM and YLX were involved in performing the experiments and collected the data. ALL, AJL, XPG and FZ analyzed the data. XPG prepared the figures and tables. ALL and AJL confirm the authenticity of all the raw data. ALL, AJL, TYZ, ZLM and YLX wrote the manuscript. XPG and FZ revised the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Approval was acquired from the Institutional Review Board (IRB) of Handan Central Hospital before the implementation of the study (approval number HDZXYY-Ethics-2021015). The requirement for written informed consent was waived by the IRB.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
AKIP1 |
A-kinase-interacting protein 1 |
|
IHC |
immunohistochemistry |
|
FIGO |
International Federation of Gynecology and Obstetrics |
|
OS |
overall survival |
|
NF |
nuclear factor |
|
EMT |
epithelial-to-mesenchymal transition |
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