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Background <p>Oral cancer continues to pose a major health problem worldwide, characterized by few treatment options and an unfavorable prognosis. The solute carrier family 15 member 4 (SLC15A4) has been reported to be associated with immune responses regulation and tumor progression. This study purpose was to reveal the role of SLC15A4 in regulating Toll-like receptor 9 (TLR9) activation and the subsequent JAK/STAT signaling pathway in the context of oral cancer progression.</p> Methods <p>Clinical samples from 38 oral cancer patients were analyzed for SLC15A4 and TLR9 expression using qPCR, Western blot, and immunohistochemistry (IHC). In vivo validation was performed using a xenograft mouse model. CAL27 and FaDu cell lines were used to study the effects of SLC15A4 knockdown on cell proliferation, migration, invasion, and inflammatory response via CCK8, ELISA, and transwell assays. SLC15A knockout and TLR9 overexpression were detected to explore their relationship with JAK/STAT signaling by detecting subcellular localization, JAK/STAT1 activation, cell invasion, migration, proliferation and inflammatory responses. The JAK/STAT agonist RO8191 was used to assess the impact of pathway activation on cell behavior.</p> Results <p>SLC15A4 was overexpressed in both tissue and cell line of oral cancer. Knockdown of SLC15A4 significantly reduced cell proliferation, migration, invasion, and inflammatory cytokine secretion (IL-6, IL-1β, TNF-α). Both STAT1 and STAT3 phosphorylation were suppressed, and JAK/STAT pathway activation restored these phenotypes. SLC15A4 knockdown also decreased TLR9 expression in cells. TLR9 overexpression restored the effects of SLC15A4 knockdown. TLR9 was shown to activate the JAK/STAT signaling pathway in oral cancer cells. Finally, activation of the JAK/STAT pathway reversed the effects of SLC15A4 knockdown.</p> Conclusion <p>SLC15A4 is essential in promoting oral cancer progression by regulating TLR9 activation and subsequent JAK/STAT signaling. This regulatory pathway influences cell proliferation, migration, invasion, and inflammation, highlighting SLC15A4 as a potential therapeutic target in treatment of oral cancer.</p>

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SLC15A4 promotes oral cancer progression by regulating TLR9 and activating the JAK/STAT signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Meiling Feng,
  • Siguleng Bayi,
  • Dema Deji,
  • Tana Han,
  • Yulan Zhang

摘要

Background

Oral cancer continues to pose a major health problem worldwide, characterized by few treatment options and an unfavorable prognosis. The solute carrier family 15 member 4 (SLC15A4) has been reported to be associated with immune responses regulation and tumor progression. This study purpose was to reveal the role of SLC15A4 in regulating Toll-like receptor 9 (TLR9) activation and the subsequent JAK/STAT signaling pathway in the context of oral cancer progression.

Methods

Clinical samples from 38 oral cancer patients were analyzed for SLC15A4 and TLR9 expression using qPCR, Western blot, and immunohistochemistry (IHC). In vivo validation was performed using a xenograft mouse model. CAL27 and FaDu cell lines were used to study the effects of SLC15A4 knockdown on cell proliferation, migration, invasion, and inflammatory response via CCK8, ELISA, and transwell assays. SLC15A knockout and TLR9 overexpression were detected to explore their relationship with JAK/STAT signaling by detecting subcellular localization, JAK/STAT1 activation, cell invasion, migration, proliferation and inflammatory responses. The JAK/STAT agonist RO8191 was used to assess the impact of pathway activation on cell behavior.

Results

SLC15A4 was overexpressed in both tissue and cell line of oral cancer. Knockdown of SLC15A4 significantly reduced cell proliferation, migration, invasion, and inflammatory cytokine secretion (IL-6, IL-1β, TNF-α). Both STAT1 and STAT3 phosphorylation were suppressed, and JAK/STAT pathway activation restored these phenotypes. SLC15A4 knockdown also decreased TLR9 expression in cells. TLR9 overexpression restored the effects of SLC15A4 knockdown. TLR9 was shown to activate the JAK/STAT signaling pathway in oral cancer cells. Finally, activation of the JAK/STAT pathway reversed the effects of SLC15A4 knockdown.

Conclusion

SLC15A4 is essential in promoting oral cancer progression by regulating TLR9 activation and subsequent JAK/STAT signaling. This regulatory pathway influences cell proliferation, migration, invasion, and inflammation, highlighting SLC15A4 as a potential therapeutic target in treatment of oral cancer.