Introduction
Multiple myeloma (MM) is a type of cancer that
occurs when plasma cells proliferate abnormally and invade the bone
marrow. MM predominantly occurs in middle-aged and elderly
individuals and its incidence rate is ~18% among all hematological
malignancies and 2% among all tumors (1). In China, the age-standardized
incidence and mortality of MM in 2019 were 0.93/100,000 and
0.67/100,000, respectively (2). In
recent years, with the emergence of bortezomib and carfilzomib, the
safety of treatments and overall survival of patients has improved
(3); however, MM remains an
incurable disease (4-6).
The mechanism underlying drug resistance remains elusive, but may
be related to epigenetic changes, apoptosis, defects in DNA damage
mechanisms and the bone marrow microenvironment (5). Therefore, identifying the molecular
mechanisms underlying MM may play an important role in developing
therapies for this disease.
PH domain leucine-rich repeat protein phosphatase 2
(PHLPP2) is a member of the PHLPP family. PHLPP family members can
dephosphorylate specific sites in protein kinase B, protein kinase
C (7) and other related factors,
thereby suppressing the inhibition of various signaling pathways.
In previous studies, PHLPP2 expression was shown to be
significantly decreased in most malignant tumors (8,9);
therefore, targeting PHLPP2 and its related genes is expected to be
identified as a potential treatment for tumors. However, in recent
years, PHLPPs has been determined to be a biological target of
small molecules, such as microRNAs (miRNAs), which play biological
roles by regulating the expression of PHLPP to indirectly affect
biological pathways involved in tumor cell proliferation,
metastasis and apoptosis. For example, miRNA-938 promotes prostate
cancer cell proliferation by inhibiting the expression of
PHLPP2(10), miRNA-760 promotes
tumor cell proliferation by downregulating PHLPP2 expression in
ovarian cancer (11), and miRNA-32
inhibits PHLPP2 expression to promote the proliferation of breast
cancer cells (12). Notably,
research on PHLPP2 has focused on cancer types such as bladder
cancer and breast cancer (13,14);
however, the expression pattern and exact mechanism involving
PHLPP2 in MM remain elusive.
In a previous study by our group, miRNA-125b was
shown to promote MM cell proliferation by suppressing the
expression of PHLPP2(15), but the
expression of PHLPP2 in patients with MM has remained to be
determined. Therefore, for the present study, plasma and bone
marrow samples were collected from newly diagnosed patients and
healthy volunteers. Subsequently, bone marrow tissue samples were
selected from patients newly diagnosed with MM for whom treatment
had been effective or ineffective. Clinical data of these patients
with MM were collected and the relationship between PHLPP2
expression and clinical features was examined. This study aimed to
evaluate the differential expression of PHLPP2 between patients
with MM and controls, to explore its potential value in MM.
Patients and methods
Patients and specimens
Plasma and bone marrow samples were obtained from 16
patients newly diagnosed with MM (9 males and 7 females; median
age, 61.5 years; age range, 42-71 years) and 16 healthy volunteers
(8 males and 8 females; median age, 52 years; age range, 35-70
years) at The First Affiliated Hospital of Nanchang University
(Nanchang, China) between April 2018 and August 2018 (consecutive
cases). In addition, paraffin-embedded specimens were obtained from
90 patients with MM at The First Affiliated Hospital of Nanchang
University between April 2016 and May 2018. The 90 patients with MM
included 54 newly diagnosed patients (33 males and 21 females;
median age, 59 years; age range, 31-83 years) and 36 treated
patients (20 males and 16 females; median age, 57.5 years; age
range, 41-71 years). The 36 patients had been treated with four
courses of chemotherapy, with concurrent efficacy evaluation and
grouping. Patients with stable disease and disease progression
after treatment were included in the ineffective group, while
patients that exhibited complete remission, very good partial
response and partial remission after treatment were included in the
effective group. A total of 15 cases (6 males and 9 females; median
age, 50 years; age range, 45-67 years) with iron deficiency anemia
(IDA) were used as controls (the samples had been collected within
6 months, these patients are all outpatient patients. The control
group wasndeliberately matched with the MM group in terms of age
and sex). Bone marrow sampling in IDA control patients was
clinically indicated to confirm iron deficiency and exclude
alternative hematological diseases. Residue specimens remaining
after routine diagnostic testing were collected for this research.
The clinical characteristics of the patients with MM are provided
in Table I.
 | Table IAssociations between the expression of
PHLPP2 in bone marrow tissue from patients with multiple myeloma
and clinical features. |
Table I
Associations between the expression of
PHLPP2 in bone marrow tissue from patients with multiple myeloma
and clinical features.
| | | PHLPP2 protein
expression | |
|---|
| Variable | N | + | - | P-value |
|---|
| Age, years | | | | 0.191 |
|
≤60 | 29 | 8 | 21 | |
|
>60 | 25 | 3 | 22 | |
| Sex | | | | 0.878 |
|
Male | 33 | 6 | 27 | |
|
Female | 21 | 5 | 16 | |
| Clinical stage | | | | 0.028 |
|
Ⅰ | 20 | 8 | 12 | |
|
II | 16 | 2 | 14 | |
|
III | 18 | 1 | 17 | |
| Immunophenotype | | | | 1.000 |
|
IgG | 26 | 5 | 21 | |
|
IgA | 18 | 4 | 14 | |
|
Light
chain | 10 | 2 | 8 | |
| β2-Microglobulin,
mg/l | | | | 0.077 |
|
≥5.5 | 18 | 1 | 17 | |
|
<5.5 | 36 | 10 | 26 | |
| HGB, g/l | | | | 0.474 |
|
≥90 | 17 | 3 | 14 | |
|
<90 | 37 | 8 | 29 | |
RNA extraction and reverse
transcription-quantitative PCR (RT-qPCR)
The mRNA expression levels of PHLPP2 were quantified
by RT-qPCR. A total of 32 samples, including 16 MM samples and 16
healthy volunteers, were evaluated by RT-qPCR. These samples
included plasma and bone marrow samples. Total RNA was isolated
using TRIzol reagent (Invitrogen; Thermo Fisher Scientific, Inc.).
The concentration of RNA in each sample was determined using an
ultraviolet NANO 2000 spectrophotometer (Thermo Fisher Scientific,
Inc.). The RNA samples obtained as aforementioned were then
subjected to RT to obtain cDNA [RNA, 2.345 µg; Oligo(dT)15 (10 µM),
2 µl; dNTP (2.5 mM), 2 µl; ddH2O (RNase free), up to
14.5 µl; with 2.0 µl of 10X RT random primers. Reaction conditions:
70˚C for 5 min, brief centrifugation and placement on ice]. The PCR
reaction mixture contained forward primer (100 µM), 0.4 µl; reverse
primer (100 µM), 0.4 µl; SYBR Green/fluorescein qPCR Master Mix
(2X) (Thermo Fisher Scientific, Inc.), 10 µl; and H2O,
5.2 µl. The reaction conditions were 50˚C for 2 min, 95˚C for 10
min; then 95˚C for 30 sec and 60˚C for 30 sec for 40 cycles. This
step was performed using a PCR instrument (ABI Q6; Applied
Biosystems; Thermo Fisher Scientific, Inc.). The primer sequences
were as follows: PHLPP2 forward, 5'-CAAGCATCCAAGGTGGTGTCC-3' and
reverse, 5'-TTGTGTCGCAAGTTGAGGTAGGTA-3'; and β-actin [which was
used as a control (16)] forward,
5'-AGCACAGAGCCTCGCCTTTG-3' and reverse, 5'-CTTCTGACCCATGCCCACCA-3'.
Fluorescence quantitative analysis was performed using qPCR (ABI
Q6). Relative PHLPP2 expression levels were determined using the
2-ΔΔCq method (17),
and the PCR experiment was performed as three independent
replicates.
Evaluation of immunohistochemical
data
Immunohistochemistry was performed using the
immunohistochemical streptavidin-peroxidase three-step method. The
main steps were as follows: Dewaxing; antigen retrieval with pepsin
(1:250 dilution; cat. no. PB390; Beijing Solarbio Science &
Technology Co., Ltd.) for 30 min at 37˚C; blockade of endogenous
peroxidase activity with 3% hydrogen peroxide (room temperature; 15
min); blocking with goat serum (5% in PBS) (Beijing Solarbio
Science & Technology Co., Ltd.) at room temperature for 30 min;
and incubation with an anti-PHLPP2 antibody (1:400 dilution; cat.
no. 25244-1-AP; Wuhan Sanying Biotechnology Co., Ltd.) at 4˚C.
After 12 h of incubation, the incubated glass slides were rinsed
with PBS three times for 3 min each time and a horseradish
peroxidase-labeled goat anti-rabbit secondary antibody (1:200; cat.
no. GB23303; Wuhan Servicebio Technology Co., Ltd.) was added to
the samples and incubated for 20 min at room temperature. Finally,
diaminobenzidine development was performed and the sections were
counterstained with hematoxylin and mounted. For negative control
images, the antibody was replaced with PBS. Cells (the cell
membrane, nucleus and cytoplasm) exhibited a brown-yellow positive
signal and the results were interpreted by semi-quantitative
assessment. A total of 10 high-power fields were randomly observed
for each section and 100 cells/field were counted for a total of
1,000 cells. The positively stained cells were scored according to
the percentage of positive cells among all cells: <5%, 0 points;
5-25%, 1 point; 26-50%, 2 points; 51-75%, 3 points; >75%, 4
points. The cell staining intensity was divided into the following
four ranges: No color, 0 points; light yellow, 1 point;
brown-yellow, 2 points; and tan, 3 points. Finally, the two results
were added to calculate the final score: 0-1 was considered
negative (-), 2-3 was considered weakly positive (+), 4-5 was
considered positive (++) and 6-7 was considered strongly positive
(+++).
Statistical analysis
The results are presented as the mean ± standard
deviation, and the data were statistically analyzed using SPSS 21.0
(IBM Corp.) and GraphPad Prism 6 (Dotmatics). Differences in PHLPP2
expression between plasma or bone marrow samples in the different
groups were analyzed with an unpaired Student's t-test. By
contrast, the relationships between clinical features and PHLPP2
expression were estimated using the χ2 test and Fisher's
exact test in Table I (P<0.05
was considered to indicate a statistically significant difference).
Bonferroni correction was used after Fisher's exact test to correct
for multiple comparisons in Table
II (original P<0.0083 was considered to indicate a
statistically significant difference).
| Table IIComparison of PHLPP2 protein
expression in bone marrow tissue in different groups. |
Table II
Comparison of PHLPP2 protein
expression in bone marrow tissue in different groups.
| | | PHLPP2 protein
expression | | |
|---|
| Sample | N | + | - | Original
P-value | Corrected
P-value |
|---|
| Control | 15 | 13 | 2 | 0.0002a | 0.0012a |
| Newly
diagnosed | 54 | 11 | 43 | 0.0077b | 0.0462b |
| Effective
treatment | 27 | 14 | 13 | 0.0317c | 0.1902c |
| Ineffective
treatment | 9 | 1 | 8 | 0.6777d | 1.000d |
Results
Expression of PHLPP2 in patient
samples
Whether bone marrow fluid or peripheral blood plasma
was examined, the mRNA expression levels of PHLPP2 were
downregulated in the samples from patients with MM compared with
those from the healthy volunteers (Fig. 1). Immunohistochemistry showed that
PHLPP2 protein was mainly located in the cytoplasm (Fig. 2). The positive rate of PHLPP2
protein expression in the bone marrow tissue of 54 newly diagnosed
patients with MM was 20.37%, which was significantly lower than
that in the bone marrow tissue of subjects with IDA (control group,
86.67%; P=0.0002). Compared with that in the newly diagnosed group,
the positive PHLPP2 expression rate in the effective-treatment
group was increased, and the differences were statistically
significant (P=0.0077). Notably, there was no significant
difference in the expression of PHLPP2 between the
ineffective-treatment group and the newly diagnosed group
(P=0.6777); and between the ineffective-treatment group and the
effective-treatment group (P=0.0317) (Table II).
Relationships between the expression
of PHLPP2 in bone marrow tissue and the clinical features of
patients with MM
The relationships between the expression of PHLPP2
in bone marrow tissue from patients with MM and their clinical
features were investigated. The analysis revealed that the positive
rate of PHLPP2 expression in bone marrow tissue samples from
patients with MM was not associated with sex or age, but it was
significantly associated with the R-ISS stage (18) (P=0.028; Table I).
Discussion
MM is a plasma cell tumor that predominantly occurs
in middle-aged and elderly individuals. MM accounts for ~18% of
hematological tumors and ~2% of all tumors (4). At present, treatment of MM is mainly
based on immunomodulators, proteasome inhibitors, histone
deacetylase inhibitors, monoclonal antibodies and signal
transduction inhibitors, which can alleviate MM; however, issues
with recurrence and drug resistance remain (5). Notably, the efficacy and safety of
chimeric antigen receptor T-cell therapy and selinexor are
currently being evaluated in clinical trials of relapsed and
refractory MM, which may provide advantages to patients with MM
(19,20). Even if these novel approaches are
effective, targeted therapies for MM will continue to play an
irreplaceable role in the treatment of this disease.
In recent years, it has been reported that the
levels of PHLPP1 and PHLPP2 are downregulated in numerous types of
cancer (9,21-25).
By contrast, certain studies have reported that loss of PHLPP2
prevents tumor growth and disease progression, and that PHLPP2
inhibitors are novel drugs that can inhibit MYC-driven cancer
(26). Notably, it has been
reported that the expression of PHLPP2 is not significantly
different among peripheral blood-derived B cells, lymphoma cell
line-derived B cells and healthy peripheral blood-derived B cells
in patients with chronic lymphocytic leukemia (27). However, it has been reported that
the expression of PHLPP2, as a major negative regulator of the
NF-κB signaling pathway, is progressively downregulated in glioma
and colorectal cancer cells, which inhibits inhibitor of NF-κB
kinase (IKBK) subunit β phosphorylation and IKBK regulatory subunit
γ ubiquitination (28). Notably,
the mechanism underlying the involvement of PHLPP2 in MM remains
elusive.
In the current study, the expression of PHLPP2 in
bone marrow and plasma specimens was examined at both the mRNA and
protein levels. Regardless of sample origin, the mRNA expression
levels of PHLPP2 were decreased in the patient group compared with
those in the control group (P<0.05), suggesting that PHLPP2 may
be association with MM; this conclusion is consistent with previous
findings on hypopharyngeal squamous cell carcinoma by Zhou et
al (29). In addition, PHLPP2
protein expression was decreased or lost in the bone marrow tissue
samples of patients with MM compared with that in the normal
control samples, as determined by immunohistochemical staining,
which is consistent with previous findings on colon cancer by Liu
et al (21). Furthermore,
the expression of PHLPP2 was associated with the R-ISS stage.
Compared with that in the newly diagnosed group and the
ineffective-treatment group, the positive expression rate was
increased in the effective-treatment group, suggesting that high
expression of PHLPP2 may be related to effective treatment in MM.
An advanced R-ISS stage is the main marker of poor prognosis in MM;
therefore, these results indicated that PHLPP2 may be a potential
prognostic marker in MM. To the best of our knowledge, the present
study is the first to investigate the clinical significance of
PHLPP2 expression in patients with MM.
Of note, it must be acknowledged that healthy bone
marrow tissue cannot be obtained from healthy volunteers, and
therefore, bone marrow tissue from patients with IDA had to be used
as a control group. Patients with IDA were selected as the optimal
comparator because their bone marrow architecture and hematopoietic
cell populations remain largely intact, with abnormalities
restricted primarily to iron metabolism and erythropoiesis, rather
than widespread marrow neoplastic or inflammatory remodeling
(30). IDA specimens were used as
controls, with inherent biases. Iron depletion may alter PHLPP2
expression via disrupted hematopoietic system redox signaling
pathway (31). Variable IDA
chronicity, underlying causes and prior iron therapy introduce
further heterogeneity. Still, IDA marrow is the optimal available
comparator, maintaining intact non-clonal architecture after
excluding other hematopoietic system diseases or inflammatory
disease. In addition, the results must be interpreted cautiously:
The differential expression of PHLPP2 cannot be solely attributed
to the target disease. Further limitations of the present study are
the absence of survival analyses due to limited sample size, and
lack of mechanistic validation.
In conclusion, the current study revealed that
PHLPP2 expression was significantly decreased in MM and the
expression levels of PHLPP2 were related to the clinical stage. It
may be assumed that low PHLPP2 expression predicted poor outcomes
in patients with MM; therefore, PHLPP2 may be a potential
prognostic marker in MM. In a further study, the sample size will
be expanded and follow-up increased, enhancing the scope of a
survival analysis and researching the function of PHLPP2 in
vitro (functional experiments of myeloma cells) and in
vivo (tumor formation experiment in nude mice) to clarify its
role in MM.
Acknowledgements
Not applicable.
Funding
Funding: The present study was supported by the International
Collaboration Fund of the Nation Science and Technology Committee
of China (grant no. 2011DFA32820) and the National Natural Science
Fund Project (grant no. 13008955).
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
JL, YJ and GC designed the study, performed the
experiments and analyzed the data. JL wrote the manuscript. GC
helped to revise the manuscript. JL and YJ checked and confirmed
the authenticity of the raw data. All authors read and approved the
final version of the manuscript, and agree to be accountable for
all aspects of the research in ensuring that the accuracy or
integrity of any part of the work are appropriately investigated
and resolved.
Ethics approval and consent to
participate
The protocol for the present study was approved by
the Medical Institutional and Clinical Research Ethics Committee of
The First Affiliated Hospital of Nanchang University [Nanchang,
China; ethics approval no. (2017) medical research no. (096)]. All
patients included in the present study provided prior written
informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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