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by claude@2026-07, 2026-07-14
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NF-κB upregulates hnRNPD, which destabilizes PTEN mRNA, activating the PI3K-AKT pathway and promoting oral cancer cell proliferation, migration, invasion, survival, and inhibiting autophagy and senescence.
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by claude@2026-07, 2026-07-14
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The paper investigates how heterogeneous ribonucleoprotein D (hnRNPD) regulates oral squamous cell carcinoma (OSCC) cell behavior, using hnRNPD knockout with transcriptome profiling and mechanistic assays in OSCC cells. It finds that hnRNPD promotes proliferation, migration, invasion, and survival, and that loss of hnRNPD leads to upregulation of PTEN and inhibition of the PI3K/AKT/mTOR axis via hnRNPD binding to an adenylate/uridylate-rich element in the PTEN 3’UTR to destabilize PTEN mRNA; hnRNPD and PTEN are negatively correlated in OSCC specimens. The hnRNPD knockout also inhibits autophagy through reduced NF-κB expression and downregulation of NF-κB transcriptional target LC3b, and induces cellular senescence, with a stated limitation implied by the focus on cell/tissue correlations rather than broader in vivo validation. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Summary Heterogeneous Ribonucleoprotein D (hnRNPD), an RNA binding protein transcriptionally upregulated by NF-κB transcription factor, is associated with poor outcome of Oral Squamous Cell Carcinoma (OSCC). However, the role of hnRNPD in OSCC remains elusive. This study reveals that hnRNPD positively affects the proliferation, migration, invasion, and survival of OSCC cells. Transcriptome profiling in hnRNPD knockout cells identified significant upregulation of PTEN and inhibition of the PI3K/AKT/mTOR axis. HnRNPD mediates the destabilization of PTEN mRNA by binding to the class II AU-Rich Element (ARE) in 3’UTR of PTEN. The expression of hnRNPD and PTEN are strongly negatively correlated in OSCC tissue specimens, further corroborating hnRNPD-mediated PTEN destabilization. The hnRNPD knockout inhibited autophagy, evident by an accumulation of autophagic vesicles and decreased autophagic flux. Mechanistically, the hnRNPD knockout reduced the expression of NF-κB, eventually downregulating its transcriptional target LC3b, a key mediator of autophagy. SA-β-Galactosidase staining in hnRNPD KO cells conclusively demonstrated the onset of cellular senescence. The present study demonstrates hnRNPD-driven positive modulation of autophagy via NF-κB, independent of the PI3K/AKT/mTOR axis, highlighting it as a novel therapeutic target for treating oral cancer. Graphical Abstract Highlights HnRNPD mediates oral cancer cell proliferation, migration, invasion, and survival. HnRNPD acts as a novel regulator of the PI3K/AKT/mTOR axis by destabilization of PTEN. NF-κB/RelA downregulated on knockout of HNRNPD, inhibiting autophagy through downregulating its transcriptional target LCB-II. HnRNPD mediates cellular senescence in oral cancer cells.
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Summary
Heterogeneous Ribonucleoprotein D (hnRNPD), an RNA binding protein transcriptionally upregulated by NF-κB transcription factor, is associated with poor outcome of Oral Squamous Cell Carcinoma (OSCC). However, the role of hnRNPD in OSCC remains elusive. This study reveals that hnRNPD positively affects the proliferation, migration, invasion, and survival of OSCC cells. Transcriptome profiling in hnRNPD knockout cells identified significant upregulation of PTEN and inhibition of the PI3K/AKT/mTOR axis. HnRNPD mediates the destabilization of PTEN mRNA by binding to the class II AU-Rich Element (ARE) in 3’UTR of PTEN. The expression of hnRNPD and PTEN are strongly negatively correlated in OSCC tissue specimens, further corroborating hnRNPD-mediated PTEN destabilization. The hnRNPD knockout inhibited autophagy, evident by an accumulation of autophagic vesicles and decreased autophagic flux. Mechanistically, the hnRNPD knockout reduced the expression of NF-κB, eventually downregulating its transcriptional target LC3b, a key mediator of autophagy. SA-β-Galactosidase staining in hnRNPD KO cells conclusively demonstrated the onset of cellular senescence. The present study demonstrates hnRNPD-driven positive modulation of autophagy via NF-κB, independent of the PI3K/AKT/mTOR axis, highlighting it as a novel therapeutic target for treating oral cancer.
Highlights
HnRNPD mediates oral cancer cell proliferation, migration, invasion, and survival.
HnRNPD acts as a novel regulator of the PI3K/AKT/mTOR axis by destabilization of PTEN.
NF-κB/RelA downregulated on knockout of HNRNPD, inhibiting autophagy through downregulating its transcriptional target LCB-II.
HnRNPD mediates cellular senescence in oral cancer cells.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵# Present affiliation.
Abbreviations
- HnRNPD
- Heterogeneous Ribonucleoprotein D
- AUF1
- Adenylate Uridylate rich RNA binding Factor 1
- PTEN
- Phosphatase, and Tension homolog
- PI3K
- phosphatidylinositol-3 kinase
- AKT
- protein kinase B
- ARE
- Adenylate Uridylate Rich Element.
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