Cell Communication and Signaling最新文献

Background: Transfer RNA-derived small RNAs (tsRNAs), including tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs), constitute a novel class of small noncoding RNAs (sncRNAs). tsRNAs have been linked to tumorigenesis and the progression of carcinogenesis; however, the precise molecular mechanism through which tRFs act in gastric cancer (GC) remains unknown.

Methods: tRF-Tyr is a potential GC tumor suppressor that was identified through high-throughput sequencing technology. The expression and subcellular localization of tRF-Tyr in GC were detected by via qRT‒PCR and FISH. RNA pull-down, mass spectrometry, RNA immunoprecipitation (RIP), dual-luciferase reporter and rescue assays were performed to explore the regulatory mechanisms through which tRF-Tyr acts in GC.

Results: tRF-Tyr was significantly downregulated and the downregulation of its mainly concentrated in the nuclei of GC cells. Functionally, tRF-Tyr inhibited the proliferation, invasiveness and migration of GC cells and promoted GC cells apoptosis in vitro; meanwhile, tRF-Tyr inhibited tumor growth in vivo. Mechanistically, tRF-Tyr bound directly to the hnRNPD protein and competitively inhibited the binding of hnRNPD to the c-Myc 3'UTR, thereby, regulating the c-Myc/Bcl2/Bax pathway and ultimately inhibiting the progression of GC.

Conclusions: This study focused on a novel GC suppressor, tRF-Tyr, and revealed a previously undiscovered mechanism that tRF-Tyr inhibits tumor progression by targeting hnRNPD. These findings provide new insight into the involvement of tRFs in GC and suggest a novel target for GC treatment.

Sepsis remains the leading cause of death in intensive care units. Despite newer antimicrobial and supportive therapies, specific treatments are still lacking. Neutrophils are pivotal components of the effector phase of the host immune defense against pathogens and play a crucial role in the control of infections under normal circumstances. In addition to its anti-infective effects, the dysregulation and overactivation of neutrophils may lead to severe inflammation or tissue damage and are potential mechanisms for poor prognosis in sepsis. This review focuses on recent advancements in the understanding of the functional status of neutrophils across various pathological stages of sepsis to explore the mechanisms by which neutrophils participate in sepsis progression and provide insights for the treatment of sepsis by targeting neutrophils.

Background: Tumor dissemination is a life-threatening event which confers to most cancer-related deaths with limited effective therapeutic option. TNFα-induced protein 2 (TNFAIP2) reveals pro-metastasis potential in several cancers. However, its definite role and underlying mechanism in oral squamous cell carcinoma (OSCC) is largely unknown.

Methods: The impact of TNFAIP2 on tumor metastasis was assessed based on the conditional knockout mouse with 4-nitroquinoline-1-oxide (4NQO) induced OSCC model through feature and immunohistochemistry analysis. To explore the specific mechanism, enrichment analysis and co-immunoprecipitation were applied. Meanwhile, the nano-hydroxyapatite (nHAp) and poly-L-lysine (PLL) based RNA interference delivery system was designed to restrict tumor dissemination.

Results: The conditional knockout Tnfaip2 in epithelium reduced tumor initiation rate, differentiation degree and cervical lymph node metastasis (LNM) in mouse exposed to 4NQO. Enrichment analysis suggested nuclear factor-kappa B (NF-κB) signaling was associated with these effects. Western blot proved that TNFAIP2 prevented the ubiquitin proteasome degradation of inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKKβ), a classical transcriptional activator protein in NF-κB signaling. Mechanistically, TNFAIP2 was demonstrated to competitively interact with kelch-like ECH-associated protein 1 (KEAP1) to avoid IKKβ from ubiquitination at K63 and proteasomal degradation subsequently, which finally sustained NF-κB signaling and facilitated tumor metastasis by enhancing epithelial-mesenchymal transition (EMT) and lymphangiogenesis. Notably, the synthetic small interfering RNA delivery systems nHAp@PLL-siTnfaip2 showed significant effect in attenuating tumor progression of OSCC mouse.

Conclusion: Above results showed TNFAIP2 promoted EMT and lymphangiogenesis of OSCC by regulating NF-κB signaling, a mechanism that was dependent on the interaction with KEAP1 competitively. The nHAp based TNFAIP2 interference might serve as a novel therapeutic in limiting OSCC metastasis.

Stress granules (SGs) are conserved messenger ribonucleoprotein (mRNP) granules that form through rapid coalescence in the cytoplasm of eukaryotic cells under stressful environments. These dynamic membrane-free organelles can respond to a variety of both intracellular and extracellular stressors. Studies have shown that stress conditions such as heat stress, arsenite exposure, and hypoxic stress can induce SGs formation. The formation of SGs helps mitigates the effects of environmental stimuli on cells, protects them from damage, and promotes cell survival. This paper focuses on the biogenesis of SGs and summarizes the role in regulating environmental stress-induced male reproductive disorders, with the aim of exploring SGs as a potential means of mitigating male reproduction disorders. Numerous studies have demonstrated that the detrimental effects of environmental stress on germ cells can be effectively suppressed by regulating the formation and timely disassembly of SGs. Therefore, regulating the phosphorylation of eIF2α and the assembly and disassembly of SGs could offer a promising therapeutic strategy to alleviate the impacts of environmental stress on male reproduction health.

Background: Hypoxia is a critical physiological and pathological condition known to influence various cellular processes, including steroidogenesis. While previous studies, including our own, have highlighted the regulatory effects of Hypoxia-Inducible Factor 1α (HIF1α) on steroid production, the specific molecular mechanisms remain poorly understood. This study investigates the role of hypoxia and HIF1α in steroid biosynthesis across multiple experimental models during acute exposure to low oxygen levels.

Methods: To assess the extent to which acute hypoxia modulates steroidogenesis, we employed several approaches, including the Y1 adrenocortical cell line, and a conditional HIF1α-deficient mouse line in the adrenal cortex. We focused on various regulatory patterns that may critically suppress steroidogenesis.

Results: In Y1 cells, hypoxia upregulated specific microRNAs in a HIF1α-dependent manner, resulting in the suppression of mRNA levels of critical steroidogenic enzymes and a subsequent reduction in steroid hormone production. The hypoxia/HIF1α-dependent induction of these microRNAs and the consequent modulation of steroid production were confirmed in vivo. Notably, using our adrenocortical-specific HIF1α-deficient mouse line, we demonstrated that the increase in miRNA expression in vivo is also directly HIF1α-dependent, while the regulation of steroidogenic enzymes (e.g., StAR and Cyp11a1) and steroid production occurs at the level of protein translation, revealing an unexpected layer of control under hypoxic/HIF1 α conditions in vivo.

Conclusions: These findings elucidate the molecular mechanisms underlying acute hypoxia/HIF1α-induced changes in steroid biosynthesis and may also be useful in developing new strategies for various steroid hormone pathologies.

Gastric cancer (GC) is a common and frequent malignant cancer of the digestive system with a poor prognosis. In addition to common therapies such as surgical resection and chemotherapy, novel biological interventions are quite valuable for research. Exosomes are extracellular vesicles (EVs) that originate from various cell types and contain proteins, RNA, DNA, and other components that transmit biological signals and mediate intercellular communication. Numerous studies have shown that exosomes shape the tumor microenvironment (TME) by affecting hypoxia, inflammation, immunity, metabolism, and interstitial changes in the tumor, playing a crucial role in the development and metastasis of GC. This article reviews the important role of exosomes in the TME of GC and explores their potential clinical applications in GC treatment.

PAK4 has been widely reported to function in somatic cells. However, its role and the underlying mechanisms in meiotic oocytes are largely unknown. Here, we show that PAK4 deficiency significantly disrupts maturational progression and meiotic apparatus in mouse oocytes. Furthermore, based on the kinase substrate binding preference and systematic functional screening, our mechanistic investigation demonstrated that PAK4 promotes cytoskeletal organization and oocyte maturation through phosphorylating serine 597 on DDX17. Of note, we identified a marked reduction of PAK4 protein in oocytes from diabetic mice. Importantly, ectopic expression of hyperphosphorylation-mimicking DDX17 mutant (DDX17-S597D) partly prevented the meiotic defects in these diabetic oocytes, indicating that the decreased phosphorylation of DDX17 due to PAK4 insufficiency is responsible for the impaired oocyte quality. In sum, these findings unveil the pivotal role of PAK4 in oocyte development and indicate a novel mechanism controlling meiotic progression and structure.

Background: Circular dorsal ruffles (CDRs) are large and rounded membrane ruffles that function as precursors of macropinocytosis. We recently reported that CDRs form in Hep3B hepatocellular carcinoma (HCC) cells, but not in Huh7 and HepG2 HCC cells or LO2 cells, suggesting that an unknown molecular mechanism implicates CDRs in Hep3B malignancy through macropinocytosis uptake of excessive extracellular nutrients. In this study, we investigated the cellular role and the mechanism of CDRs in Hep3B cells by focusing on the GTPase-activating protein ARAP1.

Methods: ARAP1 knock-out (KO) cells were generated. Confocal microscopy and high-resolution scanning electron microscopy (SEM) were used for identification of the target proteins and structure analysis, respectively. Proteasome inhibitor MG132, mitochondrial function inhibitor CCCP, ARF1 inhibitor Golgicide A, and macropinocytosis inhibitor EIPA were used to investigate the molecular mechanism. Cell proliferation and Transwell migration/invasion assays were used to investigate the role of ARAP1 in cellular malignancy.

Results: ARAP1 was localized to CDRs, which had reduced size following ARAP1 KO. CDRs comprised small vertical lamellipodia, the expression pattern of which was disrupted in ARAP1 KO cells. Extracellular solute uptake, rate of cell growth, and malignant potential were attenuated in KO cells. ARAP1 was also localized to mitochondria in Hep3B cells but not in the control cell lines. Mitochondrial fission protein was increased in KO cells. CCCP treatment blocked CDRs in Hep3B cells but not in controls. Surprisingly, ARAP1 expression level in Hep3B cells was lower than in Huh7, HepG2, and LO2 cells. MG132 treatment increased the ARAP1 levels in Hep3B cells, but not in Huh7 cells, revealing that ARAP1 is actively degraded in Hep3B cells.

Conclusions: These results strongly suggest that the aberrant expression of ARAP1 in Hep3B cells modulates CDRs via mitochondrial function, thereby resulting in excess uptake of nutrients as an initial event in cancer development. Based on these findings, we propose that the molecular mechanisms underlying the formation of CDRs, focusing on ARAP1, may serve as an effective therapeutic target in some types of HCC and cancers.

Extracellular vesicles (EVs) are relevant elements for cell-to-cell communication and are considered crucial in host-pathogen interactions by transferring molecules between the pathogen and the host during infections. These structures participate in various physiological and pathological processes and are considered promising candidates as disease markers, therapeutic reagents, and drug carriers. Both H. pylori and the host epithelial cells infected by H. pylori secrete EVs, which contribute to inflammation and the development of disease phenotypes. However, many aspects of the cellular and molecular biology of EV functions remain incompletely understood due to methodological challenges in studying these small structures. This review also highlights the roles of EVs derived from H. pylori-infected cells in the pathogenesis of gastric and extragastric diseases. Understanding the specific functions of these EVs during H. pylori infections, whether are advantageous to the host or the pathogen, may help the development new therapeutic approaches to prevent disease.

Background: Chondrocyte senescence play an essential role in osteoarthritis (OA) progression. Recent studies have shown that snoRNA-derived RNA fragments (sdRNAs) are novel regulators of post-transcriptional gene expression. However, the expression profiles and their role in post-transcriptional gene regulation in chondrocyte senescence and OA progression is unknown. Here, we determined sdRNAs expression profile and explored sdRNA-D43 role in OA and its mechanism.

Methods: We used qPCR arrays to determine sdRNAs expression in the chondrocytes of areas undamaged and damaged of the three knee OA samples. SdRNA-D43 expression was determined using quantitative reverse transcription-polymerase chain reaction and in situ hybridization. Then, bioinformatics analysis was conducted on the target genes that might be silenced by sdRNA-D43. Primary chondrocytes of damaged regions of knee OA samples were transfected with a sdRNA-D43 inhibitor or mimic to determine their functions, including in relation to mitophagy and chondrocyte senescence. Argonaute2-RNA immunoprecipitation and luciferase reporter assays were conducted to determine the target gene of sdRNA-D43. In a rat OA model induced by monosodium iodoacetate, adeno-associated virus sh-rat-sdRNA-D43 was injected into the knee joint cavity to assess its in vivo effects.

Results: sdRNA-D43 expression were upregulated in damaged areas of knee OA cartilage with increased senescent chondrocytes. sdRNA-D43 inhibited mitophagy and promoted chondrocytes senescence during OA progression. Mechanistically, sdRNA-D43 silenced the expression of both NRF1 and WIPI2 by binding to their 3'-UTR in an Argonaute2‑dependent manner, which inhibited PINK1/Parkin-mediated pathway. Additionally, injection of AAV-sh-sdRNA-D43 alleviated the progression of OA in a monosodium iodoacetate-induced rat model.

Conclusion: Our results reveal an important role for a novel sdRNA-D43 in OA progression. sdRNA-D43 improves chondrocyte senescence by negatively regulating PINK1/Parkin-mediated mitophagy pathway via dual-targeting NRF1 and WIPI2, which provide a potential therapeutic strategy for OA treatment.