Introduction
Sebaceous carcinoma (SGC) of the eyelid is a
malignant tumor arising from the meibomian or Zeiss glands
(1). SGC of the eyelid is highly
prevalent in Asia and represents the most common eyelid malignancy
(accounting for 43.7% of cases in Japan) (2). The tumor is generally resistant to
radiotherapy and chemotherapy, with complete surgical resection
remaining the mainstay of treatment. However, postoperative local
recurrence and lymph node metastasis have been reported in 6-24 and
8-21% of patients, respectively, reflecting a relatively high-grade
malignancy (3-6).
Adjuvant and combination therapies may improve prognosis; however,
the pathogenesis of SGC of the eyelid remains unexplored, and
sufficient research to guide diagnosis and treatment has not been
performed.
Several clinical and pathological factors have been
identified as poor prognostic indicators and risk factors for
postoperative recurrence in SGC of the eyelid. Clinical factors
include increased tumor diameter (6-8),
tumor localization (6,9), and delayed therapeutic intervention
due to misdiagnosis at initial presentation (10). Pathologic factors include diffuse
growth patterns, multicentric tumor origin, non-lobular pattern,
and poor differentiation (11-14).
In addition, pagetoid spread is a critical poor prognostic factor.
It is characterized by diffuse intraepithelial dissemination and a
tendency to invade the cornea and conjunctiva, complicating
complete surgical excision. Furthermore, it is frequently
misdiagnosed as chronic blepharoconjunctivitis, contributing to the
unfavorable prognosis (12,15-21).
Recent advances in genetic analyses have provided
insights into the biological pathways involved in the tumor
microenvironment and pathogenesis of SGC. Whole-genome studies
(22-25)
and microRNA profiling (26-28)
have been performed to elucidate tumor biology. These studies have
revealed recurrent genetic alterations and dysregulated miRNA
expression profiles associated with tumor proliferation, invasion,
and immune-related pathways in SGC.
Increasing evidence suggests that
immune-inflammatory pathways play a critical role in tumor invasion
and progression by shaping the tumor microenvironment (29,30).
In various malignancies, dysregulated immune responses and
immune-related signaling pathways have been implicated in
epithelial-mesenchymal transition, tumor invasiveness, and
metastatic potential (29,30). In sebaceous carcinoma, recent
genomic and transcriptomic studies have identified dysregulated
immune- and inflammation-related pathways associated with
aggressive tumor behavior and invasion (22-28).
These findings suggest that immune-inflammatory mechanisms may
contribute to the invasive behavior of SGC and provide a biological
rationale for investigating immune-related molecular networks in
this disease.
In recent years, integrated bioinformatic approaches
combining miRNA and mRNA expression data have been widely applied
to various malignancies to elucidate regulatory networks underlying
tumor invasiveness and therapeutic resistance, as well as to
identify potential diagnostic and prognostic biomarkers (29,30).
Despite these advances, controlling local recurrence
and lymph node metastasis remains challenging, and clinical
outcomes are often suboptimal. In particular, limited genetic
research has focused on the pathogenesis of pagetoid spread, a
major determinant of poor prognosis in SGC.
Our previous study published in 2021(28) primarily focused on global miRNA
expression profiling in eyelid sebaceous carcinoma. In contrast,
the present study uniquely applies an integrated miRNA-mRNA network
analysis to specifically explore the molecular mechanisms
underlying pagetoid spread, with particular emphasis on
invasion-related and immune-inflammatory pathways.
Therefore, this study aimed to elucidate the genetic
mechanisms involved in SGC of the eyelid with pagetoid spread.
Materials and methods
Patient and tissue samples
Nine patients who underwent surgical treatment for
eyelid tumors at Toyama University Hospital were included in this
study. These patients underwent surgical treatment between January
2020 and October 2024. Cases were selected based on the
availability of sufficient tumor tissue for molecular analyses and
a confirmed pathological diagnosis by histopathological
examination. Based on pathological findings, the patients were
divided into three groups, each comprising three participants: SGC
of the eyelid with pagetoid spread, SGC of the eyelid without
pagetoid spread, and normal controls. The pagetoid spread group
included an 88-year-old woman, a 74-year-old woman, and an
81-year-old man. The maximum tumor diameters in this group were 6,
7, and 8 mm, respectively, and all tumors were classified as T1
according to the American Joint Committee on Cancer (AJCC) staging
system (8th edition). Regarding histopathological growth patterns,
one case in the pagetoid spread group (a 74-year-old woman) showed
a diffuse growth pattern, whereas the remaining two cases showed a
nodular growth pattern. The non-pagetoid spread group consisted of
an 84-year-old woman, a 69-year-old woman, and an 80-year-old man.
The maximum tumor diameters and T classifications in this group
were 10 mm (T1), 6 mm (T1), and 11 mm (T2b), respectively. All
cases in the non-pagetoid spread group exhibited a nodular growth
pattern. No cases in either group showed evidence of multicentric
origin based on clinicopathological evaluation. Normal control
samples were obtained from a 72-year-old woman, a 74-year-old
woman, and a 77-year-old man, from whom normal tarsal plate tissue
was collected during free tarsal plate reconstruction. This study
was approved by the Institutional Review Board of the University of
Toyama (approval no. R2015051), and all procedures were conducted
in accordance with the tenets of the Declaration of Helsinki.
Written informed consent was obtained from all patients prior to
enrollment.
RNA extraction and quality
control
Total RNA was extracted from whole tumor tissue
samples stored at -80˚C after surgical excision, without prior
formalin fixation. Tumor-predominant areas were selected as much as
possible based on pathological evaluation; however, RNA was
extracted from whole tissue sections without manual
macrodissection, and adjacent non-neoplastic tissues may have been
partially included. Total RNA, including miRNA, was extracted from
tissue samples using the NucleoSpin miRNA kit (Macherey-Nagel GmbH
& Co., Düren, Germany) according to the manufacturer's
protocol. RNA quality and quantity were assessed using a
Bioanalyzer 2100 system with the RNA 6000 Nano kit (Agilent
Technologies, Santa Clara, CA, USA) (31).
Library preparation and RNA sequencing
(mRNA and miRNA)
Comprehensive mRNA and miRNA analyses were
subcontracted to OligoAtenta, Inc. (Tokyo, Japan) and performed
using their next-generation sequencing (NGS) service. For library
preparation, Illumina-compatible kits were used, and sequencing was
conducted with either paired-end or single-end reads on the NovaSeq
6000 system (Illumina, San Diego, CA, USA).
For mRNA analysis, mRNA was selectively extracted
and purified from total RNA. Sequencing libraries were subsequently
prepared and analyzed using 150 bp paired-end reads. The resulting
FASTQ data were processed using a standard pipeline provided by
OligoAtenta, which included adapter removal, quality assessment,
read mapping, and expression quantification. Reads were mapped to
the human reference genome (GRCh38), and gene expression levels
were normalized using transcripts per million (TPM) or fragments
per kilobase of transcript per million mapped reads.
In the miRNA analysis, small RNA libraries were
prepared, and reads of 83 nucleotides in length were obtained. Each
read contained a unique molecular identifier (UMI) and a 3' adapter
sequence, which were automatically trimmed during data processing.
Clean reads were mapped to miRbase, and UMI-based deduplication was
performed to obtain expression data normalized by reads per
million. Additional processing steps included adapter removal (N)
using Trim Galore, genome mapping with Bowtie2, file conversion via
Samtools, and annotation analysis using Strand NGS software. The
raw RNA sequencing data generated in the present study have been
deposited in the DNA Data Bank of Japan (DDBJ) Sequence Read
Archive under BioProject accession number PRJDB40390.
Raw read data processing
The first 50 bp sequences of each raw 150 bp
sequence read were extracted using Seqkit. Adaptor sequences were
subsequently trimmed from the 50 bp reads using Cutadapt.
Low-quality (Q score <20) and short reads (<10 bp) were
removed using the FASTX-Toolkit. The filtered reads were then
aligned to hg19, and miRNA annotation was performed using Strand
NGS version 3.3.
Integrated miRNA-mRNA interaction
analyses
To examine the molecular functions and interaction
networks of expressed miRNA and mRNA, combined data from the
present study and previously published datasets generated by our
group were analyzed using Ingenuity Pathways Analysis (IPA)
software (Ingenuity Systems, Redwood City, CA, USA).
Results
Identification of expressed miRNAs and
mRNAs
Before molecular analyses, clinicopathological
characteristics were reviewed to confirm the comparability of the
study groups. All pagetoid spread cases were classified as
pathological T1 according to the AJCC staging system (8th edition);
one case exhibited a diffuse growth pattern, whereas all remaining
cases in both the pagetoid and non-pagetoid groups showed a nodular
growth pattern, and no case in either group showed evidence of
multicentric origin. A total of 280,241,626 raw reads were obtained
for the entire SGC of the eyelid dataset, with each sample yielding
at least 20 million reads. This sequencing depth was sufficient to
ensure reliable miRNA and mRNA expression analyses. Quality
assessment was performed on the raw sequencing data. Low-quality
reads and adapter sequences were removed from the datasets. For
miRNA analysis, the filtered reads were aligned to the human
miRBase using Strand NGS and mapped to known miRNAs. For mRNA
analysis, quality-filtered reads were similarly mapped to the human
reference genome (GRCh38) using the STAR aligner. The transcript
expression levels were quantified as TPM. Expression variation and
functional analyses were subsequently performed on both datasets.
miRNAs with at least a 1.5-fold change and mRNAs with at least a
2.0-fold change in expression relative to control samples were
identified. The Venn diagram in Fig.
1 illustrates the number of genes with increased expression.
Fig. 1A presents the number of
upregulated mRNAs, whereas Fig. 1B
depicts the number of downregulated miRNAs known to suppress the
expression of their target genes. Compared with the control group,
789 and 2,205 mRNAs were upregulated in the non-pagetoid and
pagetoid groups, respectively, of which 62 were uniquely
upregulated in the pagetoid group. By contrast, 2,298 and 1,940
miRNAs were downregulated in the non-pagetoid and pagetoid groups,
respectively, of which 1,025 were uniquely downregulated in the
pagetoid group. The Venn diagram in Fig. 2 illustrates the number of genes
with decreased expression. Fig. 2A
and B present the numbers of
downregulated and upregulated mRNAs, respectively. Compared with
the control group, 667 and 187 mRNAs were downregulated in the
non-pagetoid and pagetoid groups, respectively, with 40 uniquely
downregulated in the pagetoid group. Conversely, 3,179 and 2,640
miRNAs were upregulated in the non-pagetoid and pagetoid groups,
respectively, of which 1,239 were uniquely upregulated in the
pagetoid group.
Functional analyses of expressed
miRNAs and mRNAs
To investigate the biological functions and
canonical pathways associated with pagetoid spread, an integrated
miRNA-mRNA dataset comprising 62 upregulated mRNAs and 1,025
downregulated miRNAs specifically identified in the pagetoid group
was analyzed using IPA software. Consequently, biological functions
with positive Z-scores (indicating predicted activation) were
predominantly associated with tumor cell infiltration and migration
(e.g., cell movement, migration, and invasion of tumor cell lines)
and with immune responses (e.g., proliferation and activation of
leukocytes and lymphocytes). The top five biological functions in
each category are presented in Tables
I and II. An integrated
dataset consisting of 40 downregulated mRNAs and 1,239 upregulated
miRNAs specifically observed in the pagetoid group was subsequently
analyzed. IPA analysis predicted the inhibition of biological
functions with negative Z-scores, particularly those related to
lipid metabolism, including lipid synthesis and fatty acid
metabolism. The top five inhibited biological functions are
presented in Table III.
 | Table ITop 5 biological functions (excluding
immune- and inflammation-related functions) associated with
differentially expressed miRNAs (|fold change| ≥1.5) and mRNAs
(|fold change| ≥2.0) in eyelid sebaceous gland carcinoma with
pagetoid spread. |
Table I
Top 5 biological functions (excluding
immune- and inflammation-related functions) associated with
differentially expressed miRNAs (|fold change| ≥1.5) and mRNAs
(|fold change| ≥2.0) in eyelid sebaceous gland carcinoma with
pagetoid spread.
| Functional
annotation | P-value | Predicted
activation state | Activation
z-score | No. of
molecules |
|---|
| Cell movement of
tumor cell lines |
5.03x10-6 | Increased | 5.635 | 54 |
| Migration of tumor
cell lines |
9.67x10-6 | Increased | 5.106 | 50 |
| Invasion of tumor
cell lines |
3.78x10-6 | Increased | 4.761 | 48 |
| Invasion of
cells |
1.93x10-6 | Increased | 4.735 | 53 |
| Cell movement |
1.01x10-11 | Increased | 4.67 | 96 |
| Table IITop 5 immune- and
inflammation-related biological functions associated with
differentially expressed miRNAs (|fold change| ≥1.5) and mRNAs
(|fold change| ≥2.0) in eyelid sebaceous gland carcinoma with
pagetoid spread. |
Table II
Top 5 immune- and
inflammation-related biological functions associated with
differentially expressed miRNAs (|fold change| ≥1.5) and mRNAs
(|fold change| ≥2.0) in eyelid sebaceous gland carcinoma with
pagetoid spread.
| Functional
annotation | P-value | Predicted
activation state | Activation
z-score | No. of
molecules |
|---|
| Leukopoiesis |
1.58x10-20 | Increased | 4.241 | 58 |
| Cytotoxicity of
leukocytes |
6.6x10-16 | Increased | 4.204 | 23 |
| Activation of
leukocytes |
2.52x10-28 | Increased | 4.19 | 63 |
| Hematopoiesis of
mononuclear leukocytes |
2.42x10-19 | Increased | 4.104 | 51 |
| Cytotoxicity of
lymphocytes |
2.35x10-15 | Increased | 4.088 | 22 |
| Table IIITop 5 inhibited biological functions,
particularly those related to lipid metabolism, associated with
differentially expressed miRNAs (|fold change| ≥1.5) and mRNAs
(|fold change| ≥2.0) in eyelid SGC with pagetoid spread. |
Table III
Top 5 inhibited biological functions,
particularly those related to lipid metabolism, associated with
differentially expressed miRNAs (|fold change| ≥1.5) and mRNAs
(|fold change| ≥2.0) in eyelid SGC with pagetoid spread.
| Functional
annotation | P-value | Predicted
activation state | Activation
z-score | No. of
molecules |
|---|
| Transport of
molecule | 0.00783 | Decreased | -3.291 | 25 |
| Fatty acid
metabolism | 0.000301 | Decreased | -2.202 | 15 |
| Transport of
lipid | 0.00429 | Decreased | -1.331 | 7 |
| Synthesis of
lipid | 0.00318 | Decreased | -1.15 | 16 |
| Absorption of
lipid | 0.000598 | Decreased | -1.123 | 4 |
Construction of molecular interaction
networks of expressed miRNAs and mRNAs
To further elucidate regulatory interactions between
miRNAs and mRNAs in the pagetoid group, target prediction analysis
was performed using the miRNA Target Filter tool in IPA.
Consequently, two miRNA-mRNA networks associated with increased
gene expression were identified: i) The invasion and migration
pathway (Fig. 3) and ii) the
immune-inflammatory response pathway (Fig. 4). Notably, both networks shared
three common target miRNAs: miR-330-5p, miR-1275, and miR-1976.
These miRNAs were consistently involved in gene expression
regulation in the pagetoid group and functioned as hub nodes,
playing central roles within the networks. Moreover, a miRNA-mRNA
network associated with lipid metabolism and gene expression
suppression was identified (Fig.
5). This network analysis suggested that five miRNAs,
miR-760-3p, miR-1266-5p, miR-3918, miR-1269a, and miR-198, were
involved in the regulation of lipid metabolism.
Discussion
Complete surgical resection is the standard
treatment for SGC of the eyelid; however, the risk of recurrence
remains relatively high even when surgery is performed with an
adequate safety margin (3-6).
Intraepithelial invasion through pagetoid spread is a major factor
contributing to local recurrence (15-19).
Therefore, elucidating the pathogenesis of SGC of the eyelid with
pagetoid spread, exploring adjuvant or combination therapies
alongside surgery, and developing diagnostic biomarkers are
essential for improving patient outcomes. In the present study, the
expression profiles of miRNAs and mRNAs specifically associated
with SGC of the eyelid with pagetoid spread were analyzed.
Integrated miRNA-mRNA datasets were analyzed to investigate the
biological functions, canonical pathways, and miRNA-mRNA networks
associated with clinicopathological features. Consequently, SGC of
the eyelid with pagetoid spread exhibited upregulated expression of
genes related to invasion, migration, and immune-inflammatory
responses, organized into interconnected regulatory networks. These
networks appear to be epigenetically regulated by miR-330-5p,
miR-1275, and miR-1976. Furthermore, downregulated expression of
genes involved in lipid metabolism was observed, with related
networks regulated by miR-760-3p, miR-1266-5p, miR-3918, miR-1269a,
and miR-198.
Several studies have examined miRNA expression in
SGC. The downregulation of miR-200c and miR-141, which regulate the
expression of ZEB1, a transcription factor involved in
epithelial-mesenchymal transition, has been associated with SGC
malignancy (32). ZEB2 has been
identified as a target of miR-651-5p, and its expression is
regulated by this miRNA (33).
Furthermore, miR-3907 promotes proliferation and migration in SGC
(34). Reduced expression of
miR-518d and miR-211, both of which suppress cell proliferation,
has also been associated with SGC (27). Additionally, miR-205 and miR-199a
have been implicated in the maintenance of cancer stemness
(26). To date, only one study has
specifically investigated miRNAs involved in SGC of the eyelid with
pagetoid spread. That study demonstrated that, compared with the
nodular type, the pagetoid type exhibited overexpression of miR-205
and downregulation of miR-199a, with corresponding overexpression
of their respective target genes EZH2 (regulated by miR-205) and
CD44 (regulated by miR-199a) (26). CD44 overexpression is recognized as
a marker of cancer stemness and has been reported to promote cell
adhesion to the extracellular matrix and migration through
epithelial-to-mesenchymal transition, thereby activating adhesion,
migration, and proliferative signaling pathways (35). These findings are consistent with
the present study, in which invasion- and migration-related
pathways were upregulated. In our previous work, miR-146a-5p,
miR-149-3p, miR-193a-3p, miR-195-5p, and miR-4671-3p were
identified as miRNAs involved in the proliferation of SGC, whereas
miR-130a-3p and miR-939-5p were associated with the suppression of
lipid metabolism (28). Thus, SGC
is regulated by miRNAs that promote proliferation, enhance invasion
and migration through epithelial-mesenchymal transition, and
suppress lipid metabolism.
Consistent with these previous findings, the present
study further demonstrated that SGC of the eyelid with pagetoid
spread exhibits greater invasive and migratory potential and a more
pronounced reduction in lipid metabolism compared with the
non-pagetoid type.
SGC with pagetoid spread was found to form specific
gene networks involving key molecules that promote cancer cell
metastasis, invasion, and proliferation. These molecules include
signal transducer and activator of transcription 1 (STAT1)
(36,37), glial cell line-derived neurotrophic
factor (38,39), interferon regulatory factor
7(40), retinoic acid-inducible
gene I (40), poly (ADP-ribose)
polymerase family member 9 (41,42),
granzyme B (43), and
interleukin-1 receptor-associated kinase 1(44).
Furthermore, SGC with pagetoid spread forms
immune-inflammatory networks, which contribute to the recruitment
and migration of immune cells, such as lymphocytes and monocytes,
and may be involved in chronic inflammation, immune evasion, and
tumor immunity. The molecules involved in this network include CC
chemokine ligand 5(45), cyclic
GMP-AMP synthase (46),
STAT1(47), interleukin-12
receptor β1 subunit (48),
hepatitis A virus cellular receptor 2(49), C-X-C motif chemokine ligand
3(50), signaling threshold
regulating transmembrane adaptor 1(51), and granzyme B (43). Notably, both the
invasion/proliferation-related and inflammation-related gene
networks were commonly regulated by three downregulated miRNAs:
miR-330-5p, miR-1275, and miR-1976. miR-1275 is downregulated in
head and neck, colorectal, and esophageal cancers, where it
regulates cancer cell migration, invasion, and proliferation
(52-54).
In pancreatic cancer, it also plays a key role in natural killer
cell function and immune evasion (55). miR-1976 is downregulated in breast
and non-small cell lung cancers, and its decreased expression has
been associated with the promotion of epithelial-mesenchymal
transition (56,57). In ovarian cancer, it has been
implicated in the regulation of tumor-infiltrating immune cells
(58). Similarly, miR-330-5p is
downregulated in non-small cell lung and papillary thyroid cancers,
where it promotes cell proliferation, migration, and invasion
(59,60). In ovarian cancer, it regulates
antigen presentation by tumor cells and immune cell infiltration
(61). Thus, the downregulation of
miR-330-5p, miR-1275, and miR-1976 are thought to play key
epigenetic roles in regulating invasion, migration, and
inflammatory immune networks in SGC with pagetoid spread.
These invasion- and migration-related networks may
not be specific to pagetoid spread alone but could also reflect
other established clinicopathological risk factors, such as tumor
size and invasive growth patterns. Likewise, the
immune-inflammatory networks identified may be related to
tumor-infiltrating lymphocytes, which are recognized as important
biological features of SGC.
SGC with pagetoid spread exhibits suppressed lipid
metabolism and forms distinct gene networks. Intracytoplasmic lipid
accumulation in SGC can be detected by immunohistochemical staining
for adipophilin or Oil Red O staining, both of which are recognized
as pathological markers of SGC (62,63).
Abnormal lipid metabolism in sebaceous glands contributes to the
development of SGC and represents a key factor in understanding its
pathogenesis. In a previous study, lipid metabolism was suppressed
in SGC compared with sebaceous adenoma (28). The present findings suggest that
SGC of the eyelid with pagetoid spread is associated with a more
pronounced dysregulation of lipid metabolism-related pathways than
the non-pagetoid type, which may be related to its higher malignant
potential. The gene network related to lipid metabolism includes
sterol-C5-desaturase (64),
cluster of differentiation 36(65), phosphatidylcholine transfer protein
(66), Niemann-Pick C1-like
1(67), glutathione S-transferase
M1(68), NADPH oxidase 5(69), stromal interaction molecule
1(70), and Na+/H+ exchanger
regulatory factor 1(71). The
downregulation of this gene network was regulated by miR-760-3p,
miR-1266-5p, miR-3918, miR-1269a, and miR-198. These miRNAs are
suggested to function as upstream regulators of genes involved in
lipid metabolism in SGC with pagetoid spread.
This study has several limitations. First, the small
sample size precluded stratified or multivariate analyses adjusting
for established high-risk clinicopathological factors, such as
tumor size, pathological T stage, diffuse growth pattern, and
multicentric origin. Although tumor size, T stage, and
multicentricity were carefully documented, the molecular
differences observed in this study may not be exclusively
attributable to pagetoid spread alone and could be influenced by
overlapping pathological features. Second, the miRNA-mRNA
interactions identified in this study were based on integrated
expression analyses and bioinformatic predictions derived from
clinical tumor specimens. Direct experimental validation of miRNA
binding to the 3' untranslated regions of target genes, such as
dual-luciferase reporter assays or functional assays using cell
line models, was not performed. Accordingly, the proposed
regulatory relationships should be considered putative, and further
functional studies using appropriate experimental models will be
required to confirm direct miRNA-mRNA interactions and their
biological effects. Third, although immune-inflammatory pathways
were identified at the transcriptomic level, no histopathological
or immunohistochemical validation of the tumor immune
microenvironment was performed. In particular, the expression of
immune checkpoint molecules such as PD-L1 and the extent of
tumor-infiltrating lymphocytes, including CD8+ T cells,
were not evaluated in this study. Therefore, the immune-related
findings should be interpreted as transcriptional alterations, and
future studies incorporating immunohistochemical analyses will be
required to clarify their pathological and clinical significance.
In addition, this study was not designed as a direct experimental
comparison between pagetoid and nodular subtypes of SGC. Rather, it
aimed to explore molecular features associated with pagetoid spread
using integrated miRNA-mRNA expression analyses; therefore, the
identified molecular networks should be interpreted as
pagetoid-associated signatures rather than definitive
subtype-specific determinants. Taken together, this study should be
regarded as an exploratory, hypothesis-generating analysis
identifying pagetoid-associated miRNA-mRNA regulatory networks in
clinical SGC specimens. These findings provide a conceptual
framework for future mechanistic and translational studies,
including functional validation in experimental models and
comprehensive clinicopathological correlation analyses.
This study provides the first comprehensive
characterization of miRNA-mRNA interaction networks in SGC of the
eyelid with pagetoid spread. Several miRNAs with altered expression
were identified, potentially regulating critical functional
changes, including enhanced invasion, migration, and inflammatory
responses, and suppressed lipid metabolism. These findings advance
the current understanding of the pathophysiological mechanisms
underlying SGC of the eyelid and may aid in the identification of
potential biomarkers and therapeutic targets. Further experimental
validation and detailed investigation are required to elucidate the
precise functional roles of these miRNA-mRNA networks associated
with pagetoid spread. Future studies are expected to clarify how
these networks contribute to improved diagnostic and therapeutic
strategies for SGC.
Acknowledgements
Not applicable.
Funding
Funding: This study was supported in part by a Grant-in-Aid for
Scientific Research (grant no. 22K09786) from the Japan Society for
the Promotion of Science.
Availability of data and materials
The data generated in the present study may be found
in the DNA Data Bank of Japan Sequence Read Archive under
BioProject accession number PRJDB40390 or at the following URL:
https://ddbj.nig.ac.jp/resource/bioproject/PRJDB40390.
The dataset is also accessible via the NCBI BioProject database at
the following URL: https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJDB40390.
Authors' contributions
TY conceived and designed the study, performed the
experiments and drafted the manuscript. TH, YF and YT contributed
to the experimental work and data acquisition. AH contributed to
the conception and design of the study, and to the interpretation
of the data. AH and YT supervised the project and provided critical
revision of the manuscript. AH and YT confirm the authenticity of
all the raw data. All authors read and approved the final
manuscript.
Ethics approval and consent to
participate
The present study was approved by the Institutional
Review Board of the University of Toyama (approval no. R2015051).
All procedures were conducted in accordance with the ethical
standards of the institutional and/or national research committee
and with the 1964 Declaration of Helsinki and its later amendments.
Written informed consent was obtained from all patients prior to
surgery, including consent for participation in the study and the
use of resected specimens for research purposes.
Patient consent for publication
Written informed consent for publication was
obtained from all patients.
Competing interests
The authors declare that they have no competing
interests.
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