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PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSKα axis

  • Authors:
    • Ou Li
    • Yuhuai Peng
    • Jinhui Che
    • Yubin Liu
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    Affiliations: Department of Hepatobiliary Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, P.R. China, Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital (The First‑Affiliated Hospital of Hunan Normal University), Changsha, Hunan 410005, P.R. China, Department of Hepatobiliary Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 125
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    Published online on: July 25, 2025
       https://doi.org/10.3892/or.2025.8958
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Abstract

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive biliary cancer originating within the liver with a high incidence, high degree of malignancy and extremely poor prognosis. Protein tyrosine phosphatase 4A1 (PTP4A1) plays a carcinogenic role in numerous tumors. However, the role of PTP4A1 in the progression of ICC has not been fully elucidated. The aim of the present study was to clarify the function of PTP4A1 in ICC. Cell Counting Kit‑8 assay, 5‑ethynyl‑2'‑deoxyuridine staining and a cell colony formation assay were performed to detect cell proliferation and viability. Wound healing and Transwell assays were used to analyze cell migration and invasion. The interaction of PTP4A1 with phosphatase and tensin homolog (PTEN) was validated by immunofluorescence and co‑immunoprecipitation assays. Reverse transcription‑quantitative PCR, western blotting and immunohistochemistry were used to evaluate the mRNA and protein expression levels. The present study demonstrated that PTP4A1 was highly expressed and associated with invasive pathological features in ICC. Furthermore, PTP4A1 promoted ICC cell proliferation, migration and invasion both in vitro and in vivo. Mechanistically, PTP4A1 interacts with PTEN, contributes to the suppression of PTEN phosphorylation and promotes the activation of the PI3K/AKT/glycogen synthase kinase 3 alpha pathway. In addition, the present results demonstrated that the promotion of cell proliferation, migration and invasion by PTP4A1 was dependent on the regulation of the PTEN/PI3K/AKT/GSk3α pathway in ICC. Collectively, these data revealed that PTP4A1 is a promising target for ICC therapeutics.
View Figures

Figure 1

PTP4A1 is highly expressed and
associated with aggressive pathological characteristics in ICC. (A)
PTP4A1 expression levels in 10 pairs of ICC tissues (T) and matched
adjacent normal tissues (N). (B) Representative images of IHC
staining for PTP4A1 in ICC tumor tissues and matched adjacent
normal tissues. (C) PTP4A1 IHC scores in ICC tumor tissues and
matched adjacent normal tissues. (D) PTP4A1 mRNA levels were
greater in ICC tissues than in adjacent normal tissues. (E-H)
Higher mRNA expression of PTP4A1 was positively associated with (E)
lymph node metastasis, (F) vascular invasion, (G) III/IV TNM stage
and (H) poor differentiation in ICC. *P<0.05 and **P<0.01.
PTP4A1, protein tyrosine phosphatase 4A1; ICC, intrahepatic
cholangiocarcinoma; IHC, immunohistochemical.

Figure 2

PTP4A1 promotes intrahepatic
cholangiocarcinoma cell proliferation in vitro and in
vivo. (A) Western blotting and (B) reverse
transcription-quantitative PCR were performed to detect PTP4A1 mRNA
and protein expression levels in RBE and HCCC-9810 cells stably
transfected with PTP4A1-OE or PTP4A1-KD lentivirus. (C and D) Cell
Counting Kit-8, (E and F) EdU and (G and H) cell colony formation
assays were used to evaluate the proliferation and viability of RBE
and HCCC-9810 cells stably transfected with PTP4A1-OE or PTP4A1-KD
lentivirus. (I) RBE and HCCC-9810 cells stably transfected with
PTP4A1-KD lentivirus and NC cells were injected into nude mice, and
subcutaneous xenograft tumors were successfully established (n=5
for each group). (J) Compared with those in the NC group, tumor
weight were significantly decreased in the PTP4A1-KD group. (K and
L) The tumor growth curves of RBE (K) and HCCC-9810 (L) cells in
nude mice. (M) Representative immunohistochemical staining for Ki67
in xenograft tumor tissues. *P<0.05 and **P<0.01. PTP4A1,
protein tyrosine phosphatase 4A1; OE, overexpression; KD,
knockdown; NC, negative control; EV, empty vector.

Figure 3

PTP4A1 promotes migration, invasion
and EMT in intrahepatic cholangiocarcinoma. (A and B) Wound healing
and (C and D) migration assays were used to detect the effect of
PTP4A1 on the migration of RBE and HCCC-9810 cells. Invasion assays
(E and F) were used to evaluate the invasion abilities of RBE and
HCCC-9810 cells stably transfected with PTP4A1-overexpressing and
PTP4A1-knockdown lentiviruses. (G) EMT marker and MMP2/MMP9
expression in RBE and HCCC-9810 cells stably transfected with
PTP4A1-OE and PTP4A1-KD lentiviruses. (H-N) Quantitative analysis
of (H) FN1, (I) E-cadherin, (J) N-cadherin, (K) Vimetin, (L) MMP9
and (N) MMP2 expression levels. (M) E-cadherin and N-cadherin
expression levels in tumorigenic tissues were measured by
immunohistochemistry. **P<0.01. PTP4A1, protein tyrosine
phosphatase 4A1; EMT, epithelial-mesenchymal transition; OE,
overexpression; KD, knockdown; NC, negative control; EV, empty
vector.

Figure 4

PTP4A1 interacts with PTEN and
regulates the activation of the PI3K/AKT/GSKα pathway. (A) Venn
diagram showing the potential PTP4A1-interacting proteins screened
by co-IP-MS based on the screening criteria of ‘1-PTP4A1-flag and
2-PTP4A1-flag not 1-PTP4A1-IgG not 2-PTP4A1-IgG’. (B) PTP4A1
colocalized with PTEN in RBE cells. (C and D) Co-IPs were performed
to confirm the association between PTP4A1 and PTEN. (E) PTP4A1
regulated the activation of the PTEN/PI3K/AKT/GSKα signaling
pathway in RBE and HCCC-9810 cells. PTP4A1, protein tyrosine
phosphatase 4A1; PTEN, phosphatase and tensin homolog; co-IP,
co-immunoprecipitation; OE, overexpression; KD, knockdown; NC,
negative control; EV, empty vector; p-, phosphorylated.

Figure 5

Inhibitory role of PTP4A1 on PTEN
phosphorylation. (A) PTEN S380A was overexpressed in the RBE and
HCCC-9810 cells. (B) Western blotting was used to detect the
expression and phosphorylation of PI3K and AKT and in PTP4A-OE RBE
and HCCC-9810 cells transfected with the phospho-mimetic PTEN
mutant plasmid (PTEN S380A). (C-H) Phospho-mimetic PTEN S380A
reversed the promoting effects of PTP4A1 on the (C and D)
proliferation, (E and F) invasion and (G and H) metastasis of RBE
and HCCC-9810 cells. **P<0.01. PTP4A1, protein tyrosine
phosphatase 4A1; PTEN, phosphatase and tensin homolog; OE,
overexpression; EV, empty vector.

Figure 6

PTP4A1 promotes intrahepatic
cholangiocarcinoma cell proliferation, migration and invasion by
regulating the PTEN/PI3K/AKT/GSk3α pathway. (A) WB was performed to
examine the expression and phosphorylation of PTEN, PI3K, AKT and
GSk3α in PTP4A-KD RBE and HCCC-9810 cells treated with the PTEN
inhibitor SF1670 or the GSK3α inhibitor SB216763. (B and C) A
5-ethynyl-2′-deoxyuridine assay was used to evaluate the effects of
the PTEN inhibitor SF1670 or the GSK3α inhibitor SB216763 on the
proliferation of PTP4A-KD RBE and HCCC-9810 cells. (D-G) SF1670 and
SB216763 attenuated the inhibitory effects of PTP4A1 knockdown on
(D and E) migration and (F and G) invasion in RBE and HCCC-9810
cells. (H) WB was used to evaluate the ERK and TGF-β signaling
pathways in RBE and HCCC-9810 cells co-treated with SF1670 or
SB216763 and TGF-β. **P<0.01. PTP4A1, protein tyrosine
phosphatase 4A1; PTEN, phosphatase and tensin homolog; WB, western
blotting; KD, knockdown; NC, negative control; p-,
phosphorylated.
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Copy and paste a formatted citation
Spandidos Publications style
Li O, Peng Y, Che J and Liu Y: PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSK&alpha; axis. Oncol Rep 54: 125, 2025.
APA
Li, O., Peng, Y., Che, J., & Liu, Y. (2025). PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSK&alpha; axis. Oncology Reports, 54, 125. https://doi.org/10.3892/or.2025.8958
MLA
Li, O., Peng, Y., Che, J., Liu, Y."PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSK&alpha; axis". Oncology Reports 54.4 (2025): 125.
Chicago
Li, O., Peng, Y., Che, J., Liu, Y."PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSK&alpha; axis". Oncology Reports 54, no. 4 (2025): 125. https://doi.org/10.3892/or.2025.8958
Copy and paste a formatted citation
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Spandidos Publications style
Li O, Peng Y, Che J and Liu Y: PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSK&alpha; axis. Oncol Rep 54: 125, 2025.
APA
Li, O., Peng, Y., Che, J., & Liu, Y. (2025). PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSK&alpha; axis. Oncology Reports, 54, 125. https://doi.org/10.3892/or.2025.8958
MLA
Li, O., Peng, Y., Che, J., Liu, Y."PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSK&alpha; axis". Oncology Reports 54.4 (2025): 125.
Chicago
Li, O., Peng, Y., Che, J., Liu, Y."PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSK&alpha; axis". Oncology Reports 54, no. 4 (2025): 125. https://doi.org/10.3892/or.2025.8958
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