Kinesin family member 2A acts as a potential prognostic marker and treatment target via interaction with PI3K/AKT and RhoA/ROCK pathways in acute myeloid leukemia
Corrigendum in: /10.3892/or.2022.8463
- Authors:
- Published online on: November 17, 2021 https://doi.org/10.3892/or.2021.8229
- Article Number: 18
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Copyright: © Liang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Acute myeloid leukemia (AML), a heterogeneous disease of, but not restricted to, the bone marrow is characterized by abnormal clonal augmentation of immature myoblasts and presents with a poor prognosis due to rapid progress (1,2). AML accounts for more than a half of leukemia-associated mortality, with a 5-year survival rate of ~27% (3). Especially, the elderly are more sensitive to the development of AML; most cases present in individuals aged >65 years, which adds the difficulty of management due to relatively poor physical condition (4). Although novel therapies have been introduced for AML treatment over past decades, limited progress has been made in enhancing patient survival profile (5,6). Hence, to develop novel treatment options for AML, its associated molecule mechanisms, such as driver genes and pathways, have been extensively studied (7,8).
Kinesins are a class of motor proteins that are key for intracellular transport of multiple materials, such as adenovirus, and participate in almost all important cellular functions (9–11). Kinesin family member 2A (KIF2A), a member of the Kinesin-13 family, regulates mitosis via supporting the formation of the bipolar spindle (12). KIF2A is promising target in the exploration of cancer pathology, as indicated by reports of its function and potential clinical utility in multiple types of cancer, including nasopharyngeal carcinoma, non-small cell lung cancer and AML (13–15). Previously, KIF2A has been shown to be correlated with clinical features of patients with AML and regulate AML cell proliferation and apoptosis, indicating that KIF2A is involved in the regulation of AML pathology (15). However, the mechanistic role of KIF2A in AML has not been fully identified.
The present study aimed to detect the effect of KIF2A on AML cell survival and chemosensitivity, as well as the pathways by which it exerts these effects.
Materials and methods
Subjects
The present study was approved by the Institutional Review Board of First Affiliated Hospital of Anhui Medical University. A total of 58 newly diagnosed patients with AML and 30 healthy subjects (56.7% males and 43.3% females) with a mean age of 53.2±6.6 years (range, 33 to 79 years) from First Affiliated Hospital of Anhui Medical University (Anhui, China) were enrolled from January 2015 to December 2018. All patients were newly diagnosed with AML rather than acute promyelocytic leukemia and were aged >18 years, without a history of other hematological malignancy or cancer or radiotherapy or chemotherapy before enrollment. The healthy subjects were all aged >18 years, recruited during scheduled bone marrow donation and blood routine indexes, tumor markers and blood biochemistry tests were normal. All subjects provided written informed consent.
Data and sample collection
After recording the clinical characteristics of patients with AML (Table I), bone marrow samples were collected before starting induction therapy. Bone marrow samples were also collected from healthy donors. Immediately following collection, bone marrow mononuclear cells (BMMCs) were isolated from bone marrow by gradient centrifugation (at 600 × g for 15 min at 25°C) using Percoll (Sigma-Aldrich; Merck KGaA), followed by reverse transcription quantitative (RT-q)PCR assay for determination of KIF2A expression levels. For patients with AML, remission status was documented following completion of the response evaluation for induction therapy. Clinical follow-up was conducted until December 31, 2019. Event-free survival (EFS) and overall survival (OS) were estimated for analysis of survival prognosis; in addition, patients with AML were divided into high- and low KIF2A expression groups according to the median value of KIF2A expression (2.638).
Cell line culture and KIF2A expression detection
Human AML cell lines, including KG-1 [American Type Culture Collection (ATCC)], Kasumi-1 (ATCC), MOLM-13 [Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ)] and OC-AML2 (DSMZ), were cultured with 90% RPMI-1640 supplemented with 10% fetal bovine serum (FBS; both Hyclone; Cytiva) according to the manufacturer's instructions. The cells were cultured in 5% CO2 at 37°C. The expression of KIF2A in AML cell lines was determined by RT-qPCR and western blotting using BMMCs from healthy subjects as the control.
KIF2A small interfering RNA (siRNA) transfection
The transfection of 50 nM negative control (NC) or KIF2A siRNA (both Shanghai GenePharma Co., Ltd.) into AML cells (KG-1 and Kasumi-1) was performed using HillyMax reagent (Dojindo Molecular Technologies, Inc.) at 37°C for 6 h. Untreated cells were labeled as Untreated cells. At 48 h after transfection, RT-qPCR, western blotting and Annexin V/propidium iodide (AV/PI) and chemosensitivity assay were performed. At 0, 24, 48 and 72 h after transfection, Cell Counting Kit-8 (CCK-8) assay was performed. The target sequence of KIF2A siRNA was 5′-GGCAAAGAGAUUGACCUGG-3′ and the scrambled sequence used for NC siRNA was 5′-AAGAACAACACAAAAGAACAG-3′.
740 Y-P incubation
The concentration of 740 Y-P (Selleck Chemicals) incubated with AML cells (KG-1 and Kasumi-1) was 25 µg/ml, and the cells were incubated for 48 h at 37°C. The transfection of NC or KIF2A siRNA was performed as aforementioned at the same time as 740 Y-P incubation. Cells were divided into five groups as follows: i) Untreated cells; ii) NC siRNA, cells transfected with NC siRNA; iii) KIF2A siRNA, cells transfected with KIF2A siRNA; iv) NC siRNA + 740 Y-P, cells were transfected with NC siRNA and incubated with 740 Y-P and v) KIF2A siRNA + 740 Y-P, cells were transfected with KIF2A siRNA and incubated with 740 Y-P. Following incubation, RT-qPCR, western blotting, CCK-8 and AV/PI and chemosensitivity assay were performed.
Ras homolog family member A (RhoA) plasmid transfection
The sequence of RhoA was obtained from the National Center of Biotechnology Information (reference no. NM_001664.4). The sequence used for NC was 5′-AACACCGAACGAGACAGGATT-3′. NC or RhoA overexpression plasmids were constructed using pcDNA3.1 vector (Shanghai GenePharma Co., Ltd.). Then, 50 nM NC or RhoA overexpression plasmid was co-transfected with 50 nM NC or KIF2A siRNA into AML cells (KG-1 and Kasumi-1) using HilyMax (Dojindo Molecular Technologies, Inc.) at 37°C for 6 h. Cells were divided into groups as follows: i) Untreated cells; ii) NC siRNA + NC plasmid, cells transfected with NC siRNA and NC overexpression plasmid; iii) KIF2A siRNA + NC plasmid, cells transfected with KIF2A siRNA and NC overexpression plasmid; iv) NC siRNA + RhoA plasmid, cells transfected with NC siRNA and RhoA overexpression plasmid and v) KIF2A siRNA + RhoA plasmid, cells transfected with KIF2A siRNA and RhoA overexpression plasmid. RT-qPCR, western blotting and CCK-8, AV/PI and chemosensitivity assay were performed 48 h after transfection.
CCK-8 assay
CCK-8 (Sigma-Aldrich; Merck KGaA) assay was performed. The KG-1and Kasumi-1 cells (3×103) were plated, and 10 µl reagent was added for 3 h. Then, the optical density value was read using a microplate reader (BioTek Instruments, Inc.) at 450 nm.
AV/PI assay
AV/PI assay was performed using an Annexin V Apoptosis Detection kit I (BD Biosciences). The KG-1and Kasumi-1 cells (1×105; 100 µl) were stained with AV (5 µl) and PI (5 µl) for 15 min at room temperature after being digested. A FACSCalibur flow cytometer (BD Biosciences) was used to analyze the cells. The data was analyzed by FlowJo 7.6 (BD Biosciences).
RT-qPCR
The extraction of total RNA from BMMCs from healthy subjects was performed using RNeasy Mini kit (Qiagen GmbH) in accordance with the manufacturer's protocol. The complementary DNA was generated using qPCR RT Master Mix (Toyobo Life Science) and 1 µg RNA. Realtime PCR Master Mix (Toyobo Life Science) was used to perform qPCR. The thermocycling conditions were as follows: 95°C for 60 sec, followed by 40 cycles of 95°C for 15 sec and 61°C for 30 sec. Relative expression was calculated via the 2−ΔΔCq method (16). The primers for KIF2A and β-actin (internal reference) were as follows: KIF2A forward, 5′-GCCGAATACATCAAGCAAT-3′ and reverse, 5′-CTCTCCAGGTCAATCTCTT-3′ and β-actin forward, 5′-TCGTGCGTGACATTAAGGAGAAG-3′ and reverse, 5′-AGGAAGGAAGGCTGGAAGAGTG-3′.
Western blot analysis
RIPA lysis buffer (Beyotime Institute of Biotechnology) was used to isolate total protein from AML cells and BMMCs from healthy subjects. The quantification of total protein was performed via BCA Protein Assay kit (Thermo Fisher Scientific, Inc.). Then, the total protein (20 µg) was separated by 4–20% SDS-PAGE (Beyotime Institute of Biotechnology) and transferred to nitrocellulose membranes (Pall Life Sciences). The membranes were then blocked with 5% BSA (Beyotime, China) at 37°C for 1 h. Afterwards, the diluted primary antibodies (4°C, overnight) and secondary antibody (37°C, 1 h) were then incubated with the membrane. Protein bands were visualized using ECL western blotting substrate (Thermo Fisher Scientific, Inc.) and quantified with ImageJ V 1.52v (National Institutes of Health). The antibodies are listed in Table SI.
Chemosensitivity assay
Following incubation as aforementioned, the KG-1and Kasumi-1 cells (5×103) were treated with different concentrations of Adriamycin (ADR; 0.0, 0.1, 0.2, 0.4, 0.8 and 1.6 µM) (Selleck Chemicals) or Arabinofuranosyl Cytidine (AraC; 0, 10, 20, 40, 80 and 160 nM) in a 96-well plate for 48 h at 37°C. Then, CCK-8 assay was performed as aforementioned.
Statistical analysis
Statistical analysis was performed using GraphPad Prism 7.02 (GraphPad Software Inc.). Data are presented as the mean ± standard deviation or median and interquartile range. Differences in expression levels between groups were determined by Kruskal-Wallis (with post hoc Dunn's multiple comparisons test) or Mann-Whitney U test. Correlation analysis was performed using Spearman's test. Receiver operating characteristic (ROC) curve analysis was used to estimate the value of KIF2A in distinguishing patients with AML from healthy donors as well as CR from non-CR AML. EFS and OS are shown as Kaplan-Meier curves and were analyzed by Log-rank test. Comparation among groups was assessed by one-way ANOVA, subsequently, the multiple comparisons were assessed by Dunnett or Tukey's test. A two-side P<0.05 was considered to indicate a statistically significant difference.
Results
Correlation of KIF2A with risk, feature and prognosis of AML
A total of patients with 58 AML (58.6% males and 41.4% females) were enrolled, with a mean age of 57.9±11.6 years (Table I). A total of 30 healthy donors were also recruited. KIF2A was upregulated in patients with AML compared with healthy donors (P<0.001; Fig. 1A). ROC analysis revealed the ability of KIF2A to differentiate between patients with AML and healthy donors, with the area under curve (AUC) of 0.922 (95% CI, 0.865-0.979; Fig. 1B). Furthermore, KIF2A was correlated with increased bone marrow blasts (P=0.018; Fig. 2A) and poor National Comprehensive Cancer Network risk classification (P=0.016; Fig. 2C) but was not correlated with FAB classification (P=0.528; Fig. 2B) in patients with AML. In addition, KIF2A was downregulated in patients with complete response (CR) compared with non-CR patients (P=0.029; Fig. 2D). ROC analysis demonstrated that KIF2A differentiated between CR and non-CR patients, with an AUC of 0.695 (95% CI, 0.529-0.861; Fig. 2E). EFS (P=0.026; Fig. 2F) exhibited a less favorable association whereas OS (P=0.092; Fig. 2G) was not significantly different between patients with high and low KIF2A expression.
KIF2A expression in AML cell lines
KIF2A mRNA expression levels were increased in AML cell lines KG-1 (P<0.01), Kasumi-1 (P<0.01), MOLM-13 (P<0.05) and OCI-AML2 (P<0.05) compared with NC cells (Fig. 3A). Protein expression of KIF2A was also elevated in KG-1 (P<0.01), Kasumi-1 (P<0.01), MOLM-13 (P<0.05) and OCI-AML2 (P<0.05) cell lines compared with NC cells (Fig. 3B and C). Expression of KIF2A mRNA and protein levels was higher in KG-1 and Kasumi-1 cell lines, thus, KG-1 and Kasumi-1 cell lines were selected for subsequent molecular experiments.
Effect of KIF2A inhibition on AML cell proliferation, apoptosis and chemosensitivity
Following transfection, KIF2A mRNA and protein relative expression levels were downregulated in KIF2A siRNA compared with NC siRNA group in KG-1 and Kasumi-1 cells (all P<0.01; Fig. 4). These data indicated that transfection of KIF2A siRNA was successful in both cell lines.
Following transfection, in KG-1 cells, KIF2A siRNA inhibited proliferation but promoted cell apoptosis (both P<0.01; Fig. 5A-C). Chemosensitivity to ADR was enhanced by KIF2A siRNA at 0.2 (P<0.05), 0.4 (P<0.01), 0.8 (P<0.05) and 1.6 µM (P<0.05; Fig. 5D). Chemosensitivity to AraC was enhanced by KIF2A siRNA at 20 (P<0.05), 40 (P<0.01), 80 (P<0.05) and 160 µM (P<0.05; Fig. 5E). In Kasumi-1 cells, KIF2A also decreased cell proliferation (P<0.05; Fig. 5F), but increased cell apoptosis (P<0.01; Fig. 5G and H). In addition, chemosensitivity to ADR was promoted by KIF2A siRNA at 0.4 (P<0.01), 0.8 (P<0.05) and 1.6 µM (P<0.05; Fig. 5I); chemosensitivity to AraC was enhanced by KIF2A siRNA at 20 (P<0.05), 40 (P<0.01), 80 (P<0.01) and 160 µM (P<0.05; Fig. 5J).
PI3K/AKT and RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling pathways are inhibited by KIF2A inhibition in AML cells
In KG-1 cells, phosphorylated (p-)PI3K (P<0.01), p-AKT (P<0.05), RhoA (P<0.05) and ROCK1 (P<0.05) protein expression levels were inhibited by KIF2A siRNA (Fig. 6A and C). Similarly, in Kasumi-1 cells, KIF2A siRNA suppressed p-PI3K (P<0.01), p-AKT (P<0.01), RhoA (P<0.01) and ROCK1 (P<0.05) protein expression levels.
PI3K/AKT pathway activation regulates proliferation, apoptosis and chemosensitivity in KIF2A-knockdown AML cells
In rescue experiments, the PI3K/AKT pathway activator (740 Y-P) elevated p-PI3K and p-AKT expression levels in both wild-type (P<0.05 and P<0.01) and KIF2A-knockdown KG-1 cells (both P<0.01; Fig. 7A and C). Additionally, PI3K/AKT pathway activator also elevated p-PI3K and p-AKT expression in both wild-type and KIF2A-knockdown Kasumi-1 cells (all P<0.01; Fig. 7B and D).
In KG-1 cells, the PI3K/AKT pathway activator increased cell proliferation but inhibited cell apoptosis and chemosensitivity to ADR and AraC (all P<0.05; Fig. 8A-E); furthermore, PI3K/AKT activation also reversed the effect of KIF2A siRNA on cell proliferation, apoptosis and chemosensitivity (all P<0.05). In Kasumi-1 cells, the PI3K/AKT pathway activator exhibited similar effects as in KG-1 cells (Fig. 8F-J).
RhoA/ROCK pathway activation regulates proliferation, apoptosis and chemosensitivity in KIF2A-knockdown AML cells
In rescue experiments, RhoA overexpression plasmid elevated RhoA and ROCK1 expression levels in both wild-type and KIF2A-knockdown KG-1 and Kasumi-1 cells (all P<0.05; Fig. 9A-D).
In both KG-1 (Fig. S1A) and Kasumi-1 cells (Fig. S1B), RhoA expression was elevated in RhoA plasmid compared with NC plasmid group, indicating successful transfection (both P<0.001). Moreover, in KG-1 cells, RhoA overexpression plasmid enhanced cell proliferation, but inhibited cell apoptosis and chemosensitivity to ADR and AraC (all P<0.05); it also eliminated the effect of KIF2A siRNA on KG-1 cell proliferation, apoptosis and chemosensitivity (P<0.05; Fig. 10A-E). In Kasumi-1 cells, RhoA overexpression plasmid showed similar effects as in KG-1 cells (Fig. 10F-J).
Discussion
Similarly to other kinesins, KIF2A is essential for cell mitosis. Moreover, KIF2A may serve as a biomarker or therapeutic target in patients with cancer, including AML (17,18). To the best of our knowledge, there is limited evidence to support the potential clinical use of KIF2A in AML. However, KIF2A has been found to be correlated with clinical features or prognosis in other types of cancer. For example, a previous study based on The Cancer Genome Atlas database demonstrated that KIF2A is upregulated in esophageal squamous cell carcinoma tissue and its expression is correlated with worse disease-free survival in patients (19). Another study observed increased expression of KIF2A in patients with gastric cancer, and KIF2A expression is associated with worse histological type, higher TNM stage, lymph node metastasis and decreased 5-year survival rate; in addition, KIF2A is also an independent predicting factor for worse prognosis in patients with gastric cancer (20). These studies indicated that KIF2A may be a prognostic biomarker for patients with cancer. However, further studies of the clinical value of KIF2A in cancer are required.
In view of the mechanistic role of KIF2A in cancer, a study revealed that KIF2A short hairpin RNA notably suppresses tumor cell proliferation, migration and invasion, and also inhibits tumor growth and metastasis in osteosarcoma mice (21). In addition, KIF2A expression is elevated in gastric cancer cells; inhibiting KIF2A expression in gastric cancer cells suppresses cell invasion via downregulating membrane type 1-matrix metalloproteinase (22). A previous study demonstrated that KIF2A presents with higher expression in grade III–IV glioma tissue compared with grade I–II glioma tissue, and KIF2A inhibition results in suppression of glioma cell proliferation, migration, invasion and promotion of apoptosis (23). A previous study revealed that in lung adenocarcinoma, KIF2A suppression decreases migration and proliferation but promotes apoptosis in A549 cells (24). These previous studies suggest that KIF2A participates in cancer pathology primarily by regulating cell function. In the present study, KIF2A was upregulated in patients with AML and positively correlated with BM blast percentage and risk classification but negatively correlated with treatment response and survival profile. It was hypothesized that KIF2A exerted its clinical effect in the pathology of AML by modulating cancer cell functions via interaction with multiple factors, as indicated by previous studies (21–24). Here, KIF2A siRNA inhibited proliferation but enhanced apoptosis, chemosensitivity to ADR and AraC and expression levels of mRNA/proteins associated with PI3K/AKT and RhoA/ROCK pathway in AML cells. These data suggested a regulatory role of KIF2A in AML.
The PI3K/AKT and RhoA/ROCK signaling pathways are involved in the development of AML, especially the PI3K/AKT signaling pathway, which has been widely studied (25,26). To the best of our knowledge, however, the role of RhoA/ROCK is less reported in AML. A previous study demonstrated that an inhibitor of both PI3K and histone deacetylase elevates the antitumor activity of venetoclax in preclinical AML mice (27). Additionally, in AML cells, Metrine® notably suppresses cell viability and enhances cell apoptosis in a time- and dose-dependent manner by downregulating the PI3K/AKT/mTOR signaling pathway (28). Another study reported that ISC-4, a PI3K/AKT signaling pathway inhibitor, decreases cell survival and clonogenicity but promotes apoptosis and sensitivity to cytarabine in AML cells; it also enhances disease progression in a mouse model of preclinical AML (29). With regard to the RhoA/ROCK signaling pathway, a study demonstrated that ROCK1 is targeted by microRNA (miR)-592 to suppress cell proliferation, migration and invasion and enhance apoptosis in AML cells (30). Moreover, a long intergenic non-coding RNA LINC00662 increases proliferation but decreases apoptosis in AML cells by activating ROCK1 via sponging of miR-340-5p (31). These previous findings identified the role of the PI3K/AKT and RhoA/ROCK signaling pathways in AML by enhancing disease progression disease via modulation of cell function, most of which are accomplished by interacting with other factors.
To the best of our knowledge, there are few reports on the regulation of PI3K/AKT and RhoA/ROCK signaling pathways by KIF2A. A previous study revealed that KIF2A inhibition enhance squamous cell carcinoma of the oral tongue (SCCOT) cell apoptosis by downregulating the PI3K/AKT signaling pathway, which indicates that KIF2A acts as a tumor promotor by activating this pathway in SCCOT (32). Another study demonstrated that silencing of KIF2A notably elevates apoptosis but decreases proliferation, migration and invasion of gastric cancer cells by mediating AKT signaling (17). To the best of our knowledge, however, no studies have reported regulation of RhoA/ROCK signaling pathway by KIF2A in AML or other types of cancer. The present study identified a role of KIF2A in the regulation of AML pathology and demonstrated that KIF2A silencing inhibited proliferation, enhanced apoptosis and chemosensitivity; it also found that KIF2A regulated the PI3K/AKT and RhoA/ROCK signaling pathways to affect the malignant behavior of AML cells. These data enriched understanding of the mechanism underlying the progression of AML and provided a basis for investigation of novel targeted therapy.
There was a limitation of the present study: Few people were willing to give bone marrow, thus, it the sample size of controls was smaller than that of patients with AML.
In conclusion, KIF2A was correlated with worse clinical features and survival profile in patients with AML; its knockdown suppressed proliferation but promoted apoptosis and chemosensitivity via inactivating PI3K/AKT and RhoA/ROCK signaling pathways in AML cells. These data suggested the potential of KIF2A as a prognostic marker and treatment target for AML management.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
RX designed the experiments. XL analyzed the data and drafted the manuscript. XL and RX confirm the authenticity of all the raw data. XL and RX revised the manuscript. Both authors read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by the Institutional Review Board of First Affiliated Hospital of Anhui Medical University (approval no. PJ2020-12-39). All subjects provided written informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
KIF2A |
kinesin family member 2A |
AML |
acute myeloid leukemia |
ADR |
Adriamycin |
RT-q |
reverse transcription-quantitative |
EFS |
Event-free survival |
OS |
overall survival |
NC |
negative control |
CCK-8 |
Cell Counting Kit-8 |
AV/PI |
Annexin V/propidium iodide |
siRNA |
small interfering RNA |
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