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SLC7A1, SGK1 and HMGB2 are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion

  • Authors:
    • Gladys Wendy Valente‑Niño
    • Hilda Jiménez‑Wences
    • Manuel Joaquín Romero‑López
    • Judit Alarcón‑Millán
    • Miguel Ángel Mendoza‑Catalán
    • Oscar Peralta‑Zaragoza
    • Daniel Hernández‑Sotelo
    • Carlos Pérez‑Plasencia
    • Gloria Fernández‑Tilapa
  • View Affiliations / Copyright

    Affiliations: Infectious Diseases and Cancer Research Laboratory, Faculty of Biological Chemical Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero 39087, Mexico, Bioactives and Cancer Research Laboratory, Faculty of Chemical‑Biological Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero 39087, Mexico, Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Cuernavaca, Morelos 62100, Mexico, Cancer Epigenetics Laboratory, Faculty of Biological Chemical Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero 39087, Mexico, Genomics Laboratory, National Cancer Institute, Mexico City 14080, Mexico
    Copyright: © Valente‑Niño et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 235
    |
    Published online on: June 20, 2025
       https://doi.org/10.3892/mmr.2025.13600
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Abstract

MicroRNA (miRNA/miR)‑124‑3p and miR‑23b‑3p are tumor suppressor miRNAs that are associated with advanced cervical cancer (CC), regulating proliferation, migration, invasion, apoptosis and metastasis; however, the identity and function of the various genes regulated by these miRNAs remain unknown. The present study predicted the specific and shared targets of miR‑124‑3p and miR‑23b‑3p, cellular processes and signaling pathways involving the predicted targets. SLC7A1 was found among the shared targets, SGK1 among the targets of miR‑124‑3p and HMGB2 as a target of miR‑23b‑3p. SLC7A1, SGK1 and HMGB2 mRNA expression was markedly increased in patients with cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and levels of SGK1 and HMGB2 were associated with CC progression. SLC7A1, SGK1 and HMGB2 interact with proteins involved in cellular processes associated with cancer progression. Overexpression of miR‑124‑3p decreased mRNA of SLC7A1 in C‑33A cells, and of SGK1 in both cell lines. Ectopic expression of miR‑23b‑3p decreased HMGB2 levels in C‑33A and CaSki, and reduced cell migration and invasion. HMGB2 knockdown experiments revealed that HMGB2 modulates migration and invasion of CC cell lines. In conclusion, the results of the present study suggest that miR‑124‑3p and miR‑23b‑3p modulate processes associated with carcinogenesis and tumor progression through their individual and shared target mRNAs and that the miR‑23b‑3p/HMGB2 axis is among the mechanisms that modulate migration and invasion in CC.
View Figures

Figure 1

Target genes of miR-124-3p,
miR-23b-3p and shared by both miRNAs. (A) The Venn diagram shows
the target mRNAs of miR-124-3p and miR-23b-3p recorded in miRDB and
TargetScan. (B) The table shows the name of the 136 genes predicted
as targets shared by miR-124-3p and miR-23b-3p. miR, microRNA; GO,
Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.

Figure 2

Functional analysis of miR-124-3p
and/or miR-23b-3p target mRNAs. (A) Biological processes and (B)
KEGG pathways enriched by genes included among the 1,884 target
transcripts of miR-124-3p and miR-23b-3p. Terms with P<0.05 were
considered statistically significant. miR, microRNA; KEGG, Kyoto
Encyclopedia of Genes and Genomes.

Figure 3

SLC7A1, SGK1 and HMGB2 are involved
in the regulation of biological processes and signaling pathways
involved in cancer progression. The PPI network represents physical
and functional interactions of (A) SLC7A1, (B) SGK1 or (C) HMGB2
with cellular proteins. Each node represents a protein and the
lines represent protein-protein interactions. The colors represent
the biological processes and signaling pathways in which the
interacting proteins participate. Blank nodes symbolize proteins
that are not involved in the aforementioned processes or pathways.
All interactions were statistically significant
(P<5.5×10−7). SLC7A1, cationic amino acid transporter
1; SGK1, serum- and glucocorticoid-induced kinase 1; HMGB2,
mobility group box 2 protein; PPI, protein-protein interaction.

Figure 4

Expression of SLC7A1, SGK1 and HMGB2
in tissues with CESC or adenocarcinoma. (A) SLC7A1, (B) SGK1 and
(C) HMGB2 mRNA levels in tissues with CESC (red; n=306) and normal
(blue; n=13) recorded on the GEPIA platform (P<0.0.5. (D)
Expression of SLC7A1, SGK1 and HMGB2 proteins in HPA-included
tissues. Images of histological sections of normal tissue biopsies,
adenocarcinoma and CESC stained by immunohistochemistry are shown.
Staining intensity was classified as negative/weak, moderate or
strong, magnification, ×100. *P<0.05. SLC7A1, cationic amino
acid transporter 1; SGK1, serum- and glucocorticoid-induced kinase
1; HMGB2, mobility group box 2 protein; CESC, cervical squamous
cell carcinoma; HPA, Human Protein Atlas; EMT,
epithelial-mesenchymal transition.

Figure 5

Relative expression of SLC7A1
in response to overexpression of miR-124-3p, miR-23b-3p or
miR-124-3p + miR-23b-3p. SLC7A1 expression levels in (A)
HaCaT, C-33A and CaSki cells without transfection; (B) C-33A and
(C) CaSki cells transfected with 100 nM of miR-124-3p, miR-23b-3p
or miR-124-3p + miR-23b-3p mimetic for 24 h. SLC7A1 mRNA
expression was normalized to GAPDH mRNA and calculated by the
2−ΔΔCq method. Data are presented as mean ± SD.
Statistical significance was determined by Welch's ANOVA
(Games-Howell test) *P<0.05; **P<0.001; ***P<0.0001;
****P<0.00001. SLC7A1, cationic amino acid transporter 1; miR,
microRNA.

Figure 6

Relative expression of SGK1 mRNA.
SGK1 mRNA levels in (A) untransfected C-33A and CaSki cells
compared with HaCaT cells and in (B) C-33A and (C) CaSki cells
transfected with 100 nM of miR-124-3p mimetic for 24 h. SGK1 mRNA
expression was normalized to GAPDH mRNA and calculated by the
2−ΔΔCq method. Data are presented as mean ± SD.
Statistical significance was determined using unpaired Student's
t-test or Welch's ANOVA (Games-Howell test). *P<0.05;
**P<0.001. SGK1, serum- and glucocorticoid-induced kinase 1 miR,
microRNA.

Figure 7

HMGB2 mRNA and protein expression in
C-33A and CaSki cells with miR-23b-3p overexpression. (A) mRNA and
(B) protein expression levels of HMGB2 in HaCaT, C-33A and CaSki
cells. mRNA expression in (C) C-33A and (D) CaSki cells transfected
with 100 nM of the miR-23b-3p mimic. Protein expression in (E)
C-33A and (F) CaSki cells transfected with 100 nM of the miR-23b-3p
mimic. mRNA and protein expression levels of HMGB2 were normalized
with GAPDH and calculated by the 2−ΔΔCt method. Data are
presented as mean ± SD. Statistical significance was determined
using Student's t-test unpaired or Welch's ANOVA (Games-Howell
test) *P<0.05; **P<0.001; ***P<0.0001; ****P<0.00001.
HMGB2, mobility group box 2 protein; miR, microRNA.

Figure 8

Overexpression of miR-23b-3p and
HMGB2 knockdown decreases migration and invasion of C-33A and CaSki
cells. Migration of (A) C-33A and (B) CaSki cells overexpressing
miR-23b-3p. Invasion of (C) C-33A and (D) CaSki cells
overexpressing miR-23b-3p. HMGB2 expression in (E) C-33A and (F)
CaSki cells transfected with 80 nM si-HMGB2. Migration of (G) C-33A
and (H) CaSki cells with HMGB2 knockdown. Invasion of (I) C-33A and
(J) CaSki cells transfected with si-HMGB2. Migration data are
expressed as percent wound closure ± SD in three independent
experiments. Migration and invasion results are shown at
magnification, ×20. *P<0.05, **P<0.001, ***P<0.0001,
****P<0.00001. miR, microRNA; HMGB2, mobility group box 2
protein; si, small interfering; ctrl, control.

Figure 9

Predicted mechanism of regulation of
cell migration and invasion through the miR-23b-3p/HMGB2 axis.
HMGB2, high mobility group box 2; RAGE, receptor for advanced
glycation endproducts; TLR, toll like receptor; miR, microRNA.
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Copy and paste a formatted citation
Spandidos Publications style
Valente‑Niño GW, Jiménez‑Wences H, Romero‑López MJ, Alarcón‑Millán J, Mendoza‑Catalán MÁ, Peralta‑Zaragoza O, Hernández‑Sotelo D, Pérez‑Plasencia C and Fernández‑Tilapa G: <em>SLC7A1</em>, <em>SGK1</em> and <em>HMGB2</em> are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion. Mol Med Rep 32: 235, 2025.
APA
Valente‑Niño, G.W., Jiménez‑Wences, H., Romero‑López, M.J., Alarcón‑Millán, J., Mendoza‑Catalán, M.Á., Peralta‑Zaragoza, O. ... Fernández‑Tilapa, G. (2025). <em>SLC7A1</em>, <em>SGK1</em> and <em>HMGB2</em> are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion. Molecular Medicine Reports, 32, 235. https://doi.org/10.3892/mmr.2025.13600
MLA
Valente‑Niño, G. W., Jiménez‑Wences, H., Romero‑López, M. J., Alarcón‑Millán, J., Mendoza‑Catalán, M. Á., Peralta‑Zaragoza, O., Hernández‑Sotelo, D., Pérez‑Plasencia, C., Fernández‑Tilapa, G."<em>SLC7A1</em>, <em>SGK1</em> and <em>HMGB2</em> are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion". Molecular Medicine Reports 32.3 (2025): 235.
Chicago
Valente‑Niño, G. W., Jiménez‑Wences, H., Romero‑López, M. J., Alarcón‑Millán, J., Mendoza‑Catalán, M. Á., Peralta‑Zaragoza, O., Hernández‑Sotelo, D., Pérez‑Plasencia, C., Fernández‑Tilapa, G."<em>SLC7A1</em>, <em>SGK1</em> and <em>HMGB2</em> are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion". Molecular Medicine Reports 32, no. 3 (2025): 235. https://doi.org/10.3892/mmr.2025.13600
Copy and paste a formatted citation
x
Spandidos Publications style
Valente‑Niño GW, Jiménez‑Wences H, Romero‑López MJ, Alarcón‑Millán J, Mendoza‑Catalán MÁ, Peralta‑Zaragoza O, Hernández‑Sotelo D, Pérez‑Plasencia C and Fernández‑Tilapa G: <em>SLC7A1</em>, <em>SGK1</em> and <em>HMGB2</em> are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion. Mol Med Rep 32: 235, 2025.
APA
Valente‑Niño, G.W., Jiménez‑Wences, H., Romero‑López, M.J., Alarcón‑Millán, J., Mendoza‑Catalán, M.Á., Peralta‑Zaragoza, O. ... Fernández‑Tilapa, G. (2025). <em>SLC7A1</em>, <em>SGK1</em> and <em>HMGB2</em> are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion. Molecular Medicine Reports, 32, 235. https://doi.org/10.3892/mmr.2025.13600
MLA
Valente‑Niño, G. W., Jiménez‑Wences, H., Romero‑López, M. J., Alarcón‑Millán, J., Mendoza‑Catalán, M. Á., Peralta‑Zaragoza, O., Hernández‑Sotelo, D., Pérez‑Plasencia, C., Fernández‑Tilapa, G."<em>SLC7A1</em>, <em>SGK1</em> and <em>HMGB2</em> are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion". Molecular Medicine Reports 32.3 (2025): 235.
Chicago
Valente‑Niño, G. W., Jiménez‑Wences, H., Romero‑López, M. J., Alarcón‑Millán, J., Mendoza‑Catalán, M. Á., Peralta‑Zaragoza, O., Hernández‑Sotelo, D., Pérez‑Plasencia, C., Fernández‑Tilapa, G."<em>SLC7A1</em>, <em>SGK1</em> and <em>HMGB2</em> are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion". Molecular Medicine Reports 32, no. 3 (2025): 235. https://doi.org/10.3892/mmr.2025.13600
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