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Mechanistic study of MUC3A in promoting progression of clear cell renal cell carcinoma via the JAK‑STAT pathway

  • Authors:
    • Yongyang Yun
    • Xing Ji
    • Shuai Hu
    • Tianyu Wu
    • Yixiao Liu
    • Zheng Li
    • Zhoujie Sun
    • Peimin Zhou
    • Lei Yang
    • Wei Yu
  • View Affiliations / Copyright

    Affiliations: Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China
    Copyright: © Yun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 114
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    Published online on: April 14, 2026
       https://doi.org/10.3892/or.2026.9119
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Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and is associated with poor prognosis. The present study identified a membrane‑associated mucin, mucin 3A (MUC3A), a transmembrane glycoprotein, as a novel oncogenic factor in ccRCC. MUC3A was found to be highly expressed in ccRCC tissues and cell lines, with elevated levels associated with worse patient survival. Functional assays demonstrated that MUC3A knockdown significantly inhibited cell proliferation, migration, invasion, and promoted apoptosis. Mechanistically, MUC3A activated the Janus kinase‑signal transducer and activator of transcription (JAK‑STAT) signaling pathway, and activation of STAT3 reversed the effects of MUC3A knockdown. These findings suggest that MUC3A facilitates ccRCC progression via JAK/STAT signaling and may serve as a potential prognostic biomarker and therapeutic target.
View Figures

Figure 1

MUC3A is aberrantly upregulated in
ccRCC and associated with poor prognosis. (A) Pan-cancer analysis
of MUC3A expression across multiple tumor types based on TCGA data,
generated using the GEPIA2 platform. Gene expression values are
presented as log2(TPM + 1). (B) Differential expression of MUC3A in
tumor and normal samples from the TCGA-KIRC cohort (523 tumor
samples vs. 72 normal samples). *P<0.05. (C) Western blotting of
MUC3A protein expression in HK-2 and RPTEC/TERT1 non-malignant
renal epithelial cell lines and ccRCC cell lines (CAKI-1, OSRC-2,
786-O and ACHN). GAPDH was used as a loading control. (D) Western
blotting of MUC3A knockdown efficiency in 786-O and OSRC-2 cells
following transient transfection with three independent siRNAs
targeting MUC3A. si-2 was selected for subsequent functional
experiments due to its superior knockdown efficiency. (E)
Kaplan-Meier OS analysis of ccRCC patients stratified into high-
and low-MUC3A expression groups using the GEPIA2 platform. (F)
Kaplan-Meier DFS analysis of ccRCC patients based on MUC3A
expression levels. Data are derived from TCGA unless otherwise
indicated. MUC3A, mucin 3A; ccRCC, clear cell renal cell carcinoma;
TCGA, The Cancer Genome Atlas; KIRC, kidney renal clear cell
carcinoma; GEPIA2, Gene Expression Profiling Interactive Analysis
2; TPM, transcripts per million; KIRC, kidney renal clear cell
carcinoma; OS, overall survival; DFS, disease-free survival; siRNA,
small interfering RNA; si-MUC3A, MUC3A-targeting siRNA; si-Ctrl,
non-targeting control siRNA; GAPDH, glyceraldehyde-3-phosphate
dehydrogenase; si-1/si-2/si-3, three independent siRNAs targeting
MUC3A.

Figure 2

MUC3A knockdown suppresses
proliferation and promotes apoptosis in ccRCC cells. (A and B) Cell
proliferation of 786-O and OSRC-2 cells following transfection with
si-MUC3A or si-Ctrl, as assessed by CCK-8 assays at the indicated
time points. (C and D) Colony formation assays showing the
clonogenic capacity of 786-O and OSRC-2 cells following MUC3A
knockdown. Representative images and quantitative analysis are
shown. (E and F) Flow cytometric analysis of apoptosis in 786-O and
OSRC-2 cells using Annexin V-FITC/PI staining following MUC3A
silencing. Representative dot plots and corresponding quantitative
results are presented. All experiments were performed with at least
three independent biological replicates (n≥3). Data are presented
as the mean ± SD. Statistical significance was determined using a
two-tailed unpaired Student's t-test. *P<0.05, **P<0.01 and
***P<0.001. MUC3A, mucin 3A; ccRCC, clear cell renal cell
carcinoma; CCK-8, Cell Counting Kit-8; si-MUC3A, MUC3A-targeting
siRNA; si-Ctrl, non-targeting control siRNA; PI, propidium iodide;
SD, standard deviation; ns, not significant.

Figure 3

MUC3A knockdown inhibits the
migration and invasion of ccRCC cells. (A) Transwell migration
assays showing the migratory capacity of 786-O and OSRC-2 cells
following MUC3A knockdown. Quantitative analysis is shown on the
right. (B) Transwell invasion assays performed using
Matrigel®-coated chambers to assess the invasive
potential of ccRCC cells after MUC3A silencing. (C) Wound healing
assays demonstrating delayed wound closure in 786-O and OSRC-2
cells transfected with si-MUC3A compared with si-Ctrl at 24 h.
Representative images and quantitative analyses are shown. Scale
bar, 100 µm. All experiments were conducted with at least three
independent biological replicates. Data are expressed as the mean ±
SD. **P<0.01 and ***P<0.001. MUC3A, mucin 3A; ccRCC, clear
cell renal cell carcinoma; si-MUC3A, MUC3A-targeting siRNA;
si-Ctrl, non-targeting control siRNA; SD, standard deviation.

Figure 4

MUC3A is associated with the
activation of the JAK-STAT signaling pathway in ccRCC. (A) KEGG
pathway enrichment analysis of genes associated with MUC3A
expression based on TCGA-KIRC transcriptomic data. (B) GSEA showing
significant enrichment of the JAK-STAT signaling pathway in ccRCC
samples with a high MUC3A expression. (C and D) Western blotting of
total and phosphorylated JAK1, JAK2 and STAT3 in 786-O and OSRC-2
cells following MUC3A knockdown. (E) Western blotting showing that
STAT3 activation by Colivelin TFA restores p-STAT3 levels in
si-MUC3A-transfected 786-O and OSRC-2 cells, accompanied by
increased Bcl-2 and decreased cleaved caspase-3 expression. (F)
Western blotting of apoptosis-related proteins Bcl-2 and cleaved
caspase-3 following MUC3A silencing. GAPDH served as a loading
control. All western blotting experiments were repeated
independently at least three times. MUC3A, mucin 3A; JAK, Janus
kinase; STAT, signal transducer and activator of transcription;
ccRCC, clear cell renal cell carcinoma; KEGG, Kyoto Encyclopedia of
Genes and Genomes; TCGA, The Cancer Genome Atlas; KIRC, kidney
renal clear cell carcinoma; GSEA, gene set enrichment analysis;
TFA, trifluoroacetate; p-, phosphorylated.

Figure 5

STAT3 activation partially rescues
the effects of MUC3A knockdown in ccRCC cells. (A and B) CCK-8
assays showing that treatment with the STAT3 agonist Colivelin TFA
partially restored the proliferation of 786-O and OSRC-2 cells
following MUC3A knockdown. (C-F) Flow cytometric analysis
demonstrating that Colivelin TFA treatment reverses the
apoptosis-promoting effect induced by MUC3A silencing in ccRCC
cells. Data are presented as the mean ± SD from at least three
independent biological replicates. Statistical significance was
assessed using Student's t-test or one-way ANOVA as appropriate.
*P<0.05, **P<0.01 and ***P<0.001. STAT3, signal transducer
and activator of transcription 3; TFA, trifluoroacetate; MUC3A,
mucin 3A; CCK-8, Cell Counting Kit-8; si-MUC3A, MUC3A-targeting
siRNA; si-Ctrl, non-targeting control siRNA; SD, standard
deviation; ANOVA, analysis of variance.
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Yun Y, Ji X, Hu S, Wu T, Liu Y, Li Z, Sun Z, Zhou P, Yang L, Yu W, Yu W, et al: Mechanistic study of MUC3A in promoting progression of clear cell renal cell carcinoma via the JAK‑STAT pathway. Oncol Rep 55: 114, 2026.
APA
Yun, Y., Ji, X., Hu, S., Wu, T., Liu, Y., Li, Z. ... Yu, W. (2026). Mechanistic study of MUC3A in promoting progression of clear cell renal cell carcinoma via the JAK‑STAT pathway. Oncology Reports, 55, 114. https://doi.org/10.3892/or.2026.9119
MLA
Yun, Y., Ji, X., Hu, S., Wu, T., Liu, Y., Li, Z., Sun, Z., Zhou, P., Yang, L., Yu, W."Mechanistic study of MUC3A in promoting progression of clear cell renal cell carcinoma via the JAK‑STAT pathway". Oncology Reports 55.6 (2026): 114.
Chicago
Yun, Y., Ji, X., Hu, S., Wu, T., Liu, Y., Li, Z., Sun, Z., Zhou, P., Yang, L., Yu, W."Mechanistic study of MUC3A in promoting progression of clear cell renal cell carcinoma via the JAK‑STAT pathway". Oncology Reports 55, no. 6 (2026): 114. https://doi.org/10.3892/or.2026.9119
Copy and paste a formatted citation
x
Spandidos Publications style
Yun Y, Ji X, Hu S, Wu T, Liu Y, Li Z, Sun Z, Zhou P, Yang L, Yu W, Yu W, et al: Mechanistic study of MUC3A in promoting progression of clear cell renal cell carcinoma via the JAK‑STAT pathway. Oncol Rep 55: 114, 2026.
APA
Yun, Y., Ji, X., Hu, S., Wu, T., Liu, Y., Li, Z. ... Yu, W. (2026). Mechanistic study of MUC3A in promoting progression of clear cell renal cell carcinoma via the JAK‑STAT pathway. Oncology Reports, 55, 114. https://doi.org/10.3892/or.2026.9119
MLA
Yun, Y., Ji, X., Hu, S., Wu, T., Liu, Y., Li, Z., Sun, Z., Zhou, P., Yang, L., Yu, W."Mechanistic study of MUC3A in promoting progression of clear cell renal cell carcinoma via the JAK‑STAT pathway". Oncology Reports 55.6 (2026): 114.
Chicago
Yun, Y., Ji, X., Hu, S., Wu, T., Liu, Y., Li, Z., Sun, Z., Zhou, P., Yang, L., Yu, W."Mechanistic study of MUC3A in promoting progression of clear cell renal cell carcinoma via the JAK‑STAT pathway". Oncology Reports 55, no. 6 (2026): 114. https://doi.org/10.3892/or.2026.9119
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