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PubMed2026

TMEM33 regulates the proliferation and migration of lung adenocarcinoma by promoting the PI3K/AKT/mTOR signaling pathway.

Lung adenocarcinoma is a common type of lung cancer with high incidence and mortality rates. TMEM33, a tumor-associated protein, has not been fully elucidated in lung adenocarcinoma. To explore the expression of TMEM33 in lung adenocarcinoma, its impact on tumor progression, and its role in the PI3K/AKT/mTOR signaling pathway. Key genes associated with lung adenocarcinoma were screened using the Gene Expression Omnibus (GEO) dataset GSE140797 in combination with a weighted correlation network analysis (WGCNA). Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on these key genes. TMEM33 expression in Lung adenocarcinoma patients was validated using data from the TCGA database. The directly interactive molecules were screened through a bioinformatics method. Cellular assays (Western Blot, CCK8, colony formation, scratch assay, Trans well assay) and a nude mouse model were used to investigate the effects of TMEM33 on cell proliferation, migration, and tumor growth. TMEM33 is highly expressed in lung adenocarcinoma tissues (P < 0.05) and associated with poor prognosis. Overexpression of TMEM33 promotes cell proliferation and migration, and activates the PI3K/AKT/mTOR signaling pathway (P < 0.01). In the nude mouse model, TMEM33 overexpression increases tumor volume (P < 0.001), and PI3K/AKT pathway inhibition suppresses these effects (P < 0.05, P < 0.01). TMEM33 acts as an oncogene in lung adenocarcinoma by activating the PI3K/AKT/mTOR pathway, providing new therapeutic targets.

Cell migration↗

PubMed2026

Resveratrol Attenuates Gemcitabine Resistance in Hepatocellular Carcinoma Cells by Inhibiting Thymidylate Synthase.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Gemcitabine (Gem) is a commonly used drug against HCC, but its efficacy is limited by the development of resistance. Resveratrol (Res), a natural polyphenol with antitumor activity, may reverse Gem resistance in HCC, although the mechanism remains unclear. METHODS: The effects of Res on the proliferation, apoptosis, cell cycle, and invasion of Hep3B and HuH-7 cells were assessed via cell counting kit-8 (CCK-8), clonogenic, flow cytometry, and Transwell assays, respectively. Potential Res targets were predicted by network pharmacology, and markers of HCC prognosis were identified from the cancer genome atlas (TCGA) data. The interaction between Res and thymidylate synthase (TYMS) was validated by molecular docking and dynamics simulation. A Gem-resistant HuH-7 cell line (HuH-7/GR) was established, and when these cells were treated with Res combined with Gem, the effect on Gem sensitivity was detected by CCK-8 assay, clonogenic assay, and flow cytometry. Finally, a subcutaneous nude mouse model of HCC was used to evaluate the in vivo effects of Res combined with Gem. RESULTS: Res inhibited HCC cell proliferation, induced apoptosis and G2/M arrest, and suppressed invasion in a concentration-dependent manner. Network pharmacology and TCGA analysis identified TYMS as an important target gene for Res. TYMS was highly expressed in HCC tissues and correlated with poor prognosis. Res treatment reduced TYMS expression, while molecular docking and simulation showed stable binding of Res to TYMS. TYMS levels were elevated in HuH-7/GR resistant cells. Res combined with Gem was found to reverse drug resistance, inhibit proliferation and colony formation, and induce apoptosis. The Res + Gem combination group showed the smallest tumor volume in the in vivo model. CONCLUSION: By attenuating Gem resistance through TYMS inhibition, Res holds promise as a clinically viable adjunct to Gem-based chemotherapy, offering a potential strategy to improve outcomes in HCC patients.

Resveratrol↗

PubMed2026

Multi-cohort integration and machine learning identify CPVL as a novel oncogenic driver in gastric cancer.

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, and the prognosis of advanced GC remains poor. Systematic identification of robust biomarkers through multi-cohort integration and computational prioritization may facilitate the discovery of novel therapeutic targets. AIM: To identify key genes associated with gastric cancer progression through integrative multi-omics analysis and to elucidate the biological functions and molecular mechanisms of the top-prioritized candidate gene. METHODS: Comprehensive bioinformatics analyses integrating The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) datasets were performed using differential expression analysis, weighted gene co-expression network analysis (WGCNA), Cox regression, and eight machine-learning algorithms to systematically identify and prioritize GC-associated hub genes. Among the identified candidates, CPVL was selected for further validation based on its diagnostic and prognostic performance. CPVL expression and clinical relevance were validated by independent datasets and immunohistochemistry. Lentiviral constructs were used to overexpress or silence CPVL in GC cell lines. Functional assays were performed, including CCK-8, colony formation, EdU incorporation, and flow cytometry, to assess cell proliferation and cell-cycle distribution. Western blotting and JAK2 inhibitor (AZD1480) rescue experiments were performed to elucidate the underlying mechanisms, and a nude mouse xenograft model was used to evaluate tumorigenicity in vivo. RESULTS: Multi-cohort screening identified five hub genes (CPVL, AADAC, BCAT1, CPXM1, and FBN1). Among them, CPVL exhibited the highest diagnostic accuracy (AUC = 0.895) and the strongest correlation with poor overall survival, and was therefore selected for mechanistic investigation. CPVL expression was markedly upregulated in GC tissues and cell lines. Functional assays demonstrated that CPVL promotes GC cell proliferation and accelerates G1/S-phase transition. Mechanistically, CPVL activated the JAK2/STAT3 signaling pathway, upregulating Cyclin D1 and CDK4 while downregulating p27. Treatment with the JAK2 inhibitor AZD1480 partially reversed these effects. In vivo, CPVL knockdown significantly inhibited tumor growth. CONCLUSION: Through systematic multi-cohort integration and machine-learning prioritization, CPVL was identified as a novel oncogenic driver in gastric cancer. CPVL promotes tumor growth via activation of the JAK2/STAT3 pathway and regulation of the Cyclin D1/CDK4/p27 axis, highlighting its potential as a diagnostic biomarker and therapeutic target.

Biomarker↗

PubMed2026

Exon 21 skipping in ARHGAP10: A splicing switch that governs breast cancer metastasis.

Rho GTPase-activating protein 10 (ARHGAP10) is recognized as a tumor suppressor, yet the functional impact of its alternative splicing isoforms on breast cancer metastasis remains unclear. This study aimed to elucidate the role and regulatory mechanism of ARHGAP10 exon 21 skipping in breast cancer progression. Our research results indicate that in metastatic breast cancer cells, the full-length isoform ARHGAP10-L is downregulated, whereas the truncated ARHGAP10-S is upregulated. The RNA-binding protein HNRNPA0 directly binds to intron 21 of ARHGAP10 pre-mRNA, promoting exon-21 skipping and ARHGAP10-S production. Functionally, ARHGAP10-L and ARHGAP10-S exert opposing effects on breast cancer cell malignancy: ARHGAP10-L suppresses migration, invasion, and lung metastasis, whereas ARHGAP10-S promotes these aggressive phenotypes. Moreover, ARHGAP10-S exhibits enhanced binding to CDC42 and is associated with increased AKT phosphorylation. In a nude mouse model, HNRNPA0 drove lung metastasis by upregulating ARHGAP10-S. These findings establish the HNRNPA0-ARHGAP10 splicing axis as a key regulator of breast cancer metastasis, in which ARHGAP10-S promotes progression via the AKT pathway whereas ARHGAP10-L acts as a tumor suppressor, highlighting the therapeutic potential of targeting this splicing event to combat metastasis.

ARHGAP10 (RhoGTPase activating protein 10)↗

PubMed2026

Non-structural maintenance of chromosome condensin I complex subunit H knockdown suppresses malignant progression of esophageal squamous cell carcinoma via the Wnt/β-catenin signaling pathway.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) remains a major cause of cancer-related mortality, and effective therapeutic targets are still limited. Non-structural maintenance of chromosome condensin I complex subunit H (NCAPH) has been implicated in tumorigenesis; however, its clinical relevance, functional roles, and underlying mechanisms in ESCC are not fully defined. We aimed to characterize the expression pattern, prognostic value, biological functions, and mechanistic basis of NCAPH in ESCC. METHODS: Public datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to evaluate NCAPH expression and clinical associations. Single-cell RNA sequencing (scRNA-seq) data were used to map cell-type-specific distribution of NCAPH in tumor and adjacent tissues. NCAPH was silenced in KYSE150 and KYSE510 cells using lentiviral short hairpin RNAs (shRNAs), followed by Cell Counting Kit-8 (CCK-8), colony formation, wound-healing, and Transwell migration/invasion assays. A nude mouse xenograft model was established to assess the effect of NCAPH knockdown in vivo. RNA sequencing (RNA-seq), quantitative polymerase chain reaction (qPCR), western blotting, and enzyme-linked immunosorbent assay (ELISA) were performed to explore potential mechanisms. RESULTS: NCAPH was consistently upregulated in ESCC across multiple cohorts and was associated with unfavorable clinicopathological features and poorer survival. Functional assays demonstrated that NCAPH knockdown significantly inhibited ESCC cell proliferation, migration, invasion, and clonogenic growth. In vivo, NCAPH silencing suppressed xenograft tumor growth. Mechanistically, transcriptomic profiling and molecular validation indicated attenuation of Wnt/β-catenin signaling following NCAPH depletion, accompanied by reduced β-catenin and downstream targets. CONCLUSIONS: NCAPH promotes malignant progression of ESCC, at least in part through activation of the Wnt/β-catenin pathway, and may serve as a potential biomarker and therapeutic target.

Esophageal squamous cell carcinoma (ESCC)↗

PubMed2026

Apolipoprotein E promotes papillary thyroid carcinoma progression by activating PINK1/Parkin-mediated mitophagy.

BACKGROUND: Increasing evidence supports a progression-related role of apolipoprotein E (APOE) in papillary thyroid carcinoma (PTC), yet a clear mechanistic explanation for this association is still lacking. Considering the pivotal role of mitochondrial homeostasis in tumorigenesis, the potential role of APOE in promoting PTC progression through mitophagy regulation was investigated. Additionally, the involvement of the PINK1/Parkin-associated pathway in this process was examined to provide insights into its contribution to tumor progression. METHODS: APOE in thyroid carcinoma was characterized in terms of its expression profile, diagnostic relevance, and potential biological functions, based on integrative evidence derived from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. APOE and mitophagy-related protein expression were further examined in PTC tissues by immunohistochemistry. Further evaluation of APOE in PTC cell lines focused on its association with proliferation, apoptosis, and mitophagy, with bidirectional functional perturbation serving as the basis for assessment. Pharmacological inhibitors were used to assess the involvement of mitophagy-related signaling in the observed APOE-dependent phenotypes. Additionally, the in vivo impact of APOE on PTC tumor growth and mitophagy was further investigated through a nude mouse xenograft model, providing insight into its potential role in tumor progression. RESULTS: A significant upregulation of APOE was observed in thyroid carcinoma tissues and PTC cell lines, supporting its potential relevance as a diagnostic biomarker. The modulation of APOE expression significantly influenced PTC cell proliferation and apoptosis, with overexpression promoting cell proliferation and inhibiting apoptosis, while knockdown led to the opposite effects. Mechanistically, APOE overexpression increased AMP-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation, accompanied by increased PINK1 and Parkin expression and mitophagy-related changes, including altered mitochondrial membrane potential, reduced overall reactive oxygen species levels, and increased autophagosome formation. Pharmacological inhibition of mitophagy attenuated the proliferative and antiapoptotic effects of APOE. CONCLUSIONS: These findings demonstrate that APOE promotes PTC progression in association with PINK1/Parkin-related mitophagy and modulation of the AMPK/mTOR axis. The APOE-associated mitophagy axis may provide a rationale for future preclinical investigation in PTC.

Apolipoprotein E (APOE)↗

PubMed2026

Four-dimensional molecular mapping from a spatial snapshot reveals the dynamics of hair follicle organogenesis.

Understanding organ formation requires capturing molecular information simultaneously in three-dimensional (3D) space and across developmental time. To this end, we developed 3D DNase-Enhanced Expression Profiling (3DEEP), a tissue-clearing approach that removes genomic DNA to extend spatial transcriptomic profiling hundreds of microns into intact tissues. We applied 3DEEP to neonatal mouse skin, capturing hundreds of developing hair follicles across their organogenesis trajectory. Ordering follicles by molecularly inferred developmental age transformed this single spatial snapshot into a four-dimensional (3D + time) molecular map of organogenesis. This map revealed developmental dynamics spanning stem cell compartment stratification, emergence of new cell subtypes within the follicle, and cascading structural transformations leading to hair canal formation. Comparative analysis of Foxn1-deficient nude mice, a hairlessness model, revealed organ-wide changes in developmental dynamics, including delayed molecular progression, reduced coordination, and increased developmental instability, preceding overt structural defects. This work demonstrates how deep-tissue spatial transcriptomics can uncover hidden dynamics of organ formation.

Animals↗

PubMed2025

Amylin inhibits gastric cancer progression by targeting CCN1 and affecting the PI3K/AKT signalling pathway.

METHODS: This study used a combination of in vitro and in vivo experiments to investigate the role of amylin in the progression of GC. The expression of amylin in GC and its clinical correlation were evaluated using 38 pairs of GC and healthy human clinical samples. In vitro studies, human GC cell lines were treated with amylin to evaluate the effects of amylin on the proliferation, apoptosis and migration of GC cells. In in vivo studies, xenograft mouse models were established by subcutaneous injection of GC cells into nude mice, followed by treatment with amylin to assess tumor growth. Finally, Next-Generation Sequencing Technology (RNA-seq) was used to explore the potential mechanism of amylin on GC. RESULTS: We found that amylin expression was reduced in GC compared to adjacent normal gastric tissues and that elevated amylin expression was negatively correlated with adverse pathological factors (p < 0.05). Additionally, we demonstrated that amylin impeded the growth, invasion, migration, and colony formation of GC cells and suppressed the epithelial-to-mesenchymal transformation of these cells (p < 0.05). Tumour xenograft model experiments confirmed the tumour-suppressive effect of amylin in subcutaneous tumours in nude mice (p < 0.05). Transcriptome sequencing (RNA-seq) revealed that amylin significantly down-regulated CCN1 gene expression in GC cells (p < 0.001). Further intervention targeting CCN1 verified its significance as a target of amylin's anti-carcinogenic function in GC. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that amylin exerted its oncogenic effects by inhibiting the PI3K/Akt signalling pathway (p < 0.05). CONCLUSIONS: Our findings demonstrate that amylin plays a crucial role in suppressing gastric cancer progression by targeting CCN1 and inhibiting the PI3K/Akt signalling pathway. These results suggest that amylin could serve as a potential therapeutic agent for GC treatment.

Humans↗

PubMed2026

In vitro and in vivo studies on the impact of the familial adenomatous polyposis heterogeneous mutation MUC20-S671C on colorectal carcinogenesis and progression.

BACKGROUND: Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer (CRC). We performed genetic testing on nine FAP patients and identified a recurrent mutation at the 671st site of the MUC20 gene-MUC20-S671C. This mutation has a detection frequency of zero in the 1000 Genomes Project database. Previous studies have demonstrated that MUC20 can promote CRC progression through epithelial-mesenchymal transition (EMT). We conducted a series of experiments to analyze the impact of this mutation on CRC cells, aiming to infer its potential role and significance in CRC patients. METHODS: We introduced the MUC20-S671C mutation into the CRC SW480 cell line using the CRISPR-Cas9 technique and established a stable cell line carrying this mutation. We then conducted various experiments to assess the effects of this mutation. The Transwell assay was used to evaluate cell invasion and migration. We also examined cell proliferation, cell cycle progression, and apoptosis rate. Furthermore, we tested the tumorigenic ability of these cells in NOD-scid IL2Rγ[null] (NSG) mice. Additionally, transcriptome sequencing was performed on both cell lines and mouse tumor tissues to obtain molecular regulatory network data, and key molecules were further validated. RESULTS: The results of Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assays indicated that the proliferation ability of mutant cells was significantly reduced. The Transwell assay demonstrated a marked decline in the invasion and migration capabilities of mutant cells. Flow cytometry analysis revealed that the mutation increased the apoptosis rate of CRC cells and might have caused S-phase arrest. The tumor formation assay in nude mice showed that the tumorigenic ability of mutant cells was weakened. Transcriptome sequencing of both the cells and tumor tissues suggested that the mutation altered the expression of apoptosis- and cell cycle-related molecules and also affected EMT. Further experiments confirmed that key molecules involved in the EMT process, such as E-cadherin, were upregulated, while Vimentin, MMP9, and MMP14 were significantly downregulated, indicating that the mutation weakened the EMT capability of CRC cells. CONCLUSIONS: We have identified a novel mutation, MUC20-S671C, in patients with FAP. Our study demonstrates that this mutation exerts its tumor-suppressive effect by reversing the EMT process.

MUC20-S671C↗

PubMed2025

Therapeutic targeting of WDR5-MLL1 by EMBOW-derived peptides suppresses leukemia progression.

WD40 repeat-containing protein 5 (WDR5) is a core component of the SET1/mixed lineage leukemia (MLL) complex that regulates gene expression via H3K4 methylation and plays a key role in maintaining oncogenic gene expression programs, particularly in MLL1-rearranged leukemias. In this study, we leveraged a microprotein, endogenous microprotein binder of WDR5 (EMBOW), to develop peptide-based inhibitors that specifically targeted WDR5. Through comprehensive biophysical analyses and high-resolution structural studies, we revealed that EMBOW mainly bound to the WDR5 interaction (WIN) site of WDR5. Structure-guided optimization led to the development of EMBOW-derived peptides, notably Ac7, which exhibited high affinity for WDR5 (Kd = 9.17 ± 4.01 nM). These peptides effectively inhibited H3K4 methylation, suppressed oncogenic gene expression, and impeded leukemia cell proliferation in vitro. Importantly, in xenograft mouse models, Ac7 demonstrated significant anti-tumor activity with low toxicity. This work offers a promising strategy for targeting epigenetic regulators with peptide-based therapeutics, providing a foundation for innovative treatments in leukemia.

Humans↗

PubMed2024

The AKR1C1-CYP1B1-cAMP signaling axis controls tumorigenicity and ferroptosis susceptibility of extrahepatic cholangiocarcinoma.

Extrahepatic cholangiocarcinoma (ECC), a highly malignant type of cancer with increasing incidence, has a poor prognosis due to limited treatment options. Based on genomic analysis of ECC patient samples, here we report that aldo-keto reductase family 1 member C1 (AKR1C1) is highly expressed in human ECC tissues and closely associated with ECC progression and poor prognosis. Intriguingly, we show that inducible AKR1C1 knockdown triggers ECC cells to undergo ferroptosis. Mechanistically, AKR1C1 degrades the protein stability of the cytochrome P450 family member CYP1B1, a newly discovered mediator of ferroptosis, via ubiquitin-proteasomal degradation. Additionally, AKR1C1 decreases CYP1B1 mRNA level through the transcriptional factor aryl-hydrocarbon receptor (AHR). Furthermore, the AKR1C1-CYP1B1 axis modulates ferroptosis in ECC cells via the cAMP-PKA signaling pathway. Finally, in a xenograft mouse model of ECC, AKR1C1 depletion sensitizes cancer cells to ferroptosis and synergizes with ferroptosis inducers to suppress tumor growth. Therefore, the AKR1C1-CYP1B1-cAMP signaling axis is a promising therapeutic target for ECC treatment, especially in combination with ferroptosis inducers.

Humans↗

PubMed2026

LDHC4 promotes ovarian cancer progression through H4K12 lactylation to regulate PGK1 expression and modulate glycolysis.

OBJECTIVE: Ovarian cancer (OC) pathogenesis involves metabolic and epigenetic alterations, yet the underlying mechanisms remain unclear. Here, we sought to investigate the role and regulatory mechanism of lactate dehydrogenase C4 (LDHC4) in OC progression. METHODS: Multi-omics approaches were employed, including analyses of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts, tissue microarrays, molecular biology experiments, and in vivo mouse models. LDHC4 expression was modulated in OC cell lines (A2780 and ES-2) to assess its effects on proliferation, migration, invasion, and metastasis. Lactylproteomic profiling, cleavage under targets and tagmentation (CUT&Tag), and chromatin analyses were conducted to explore epigenetic mechanisms. The functional role of the downstream glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was examined using pharmacological inhibition. Molecular docking and xenograft models were used to evaluate the therapeutic potential of targeting H4K12lac (lactylation of histone H4 at lysine 12). RESULTS: LDHC4 was significantly overexpressed in OC tissues and associated with poor overall survival (OS) (hazard ratio [HR] = 4.017, 95% confidence interval [CI]: 2.308–6.989, P < 0.0001). It promoted proliferation, migration, invasion, and metastasis in vitro and in vivo. LDHC4 overexpression increased global lactylation, notably upregulating H4K12lac, which was enriched at the PGK1 promoter. Inhibition of PGK1 with CBR-470-1 (half-maximal inhibitory concentration [IC₅₀] = 14.56 µM) suppressed OC growth and metastasis. Importantly, Elbasvir, identified as a high-affinity H4K12lac inhibitor, significantly reduced tumor burden in mouse xenografts across multiple doses (10–20 mg·kg⁻¹) and downregulated H4K12lac and Ki-67 expression. CONCLUSION: We conclude that LDHC4 promotes OC progression via lactylation-mediated epigenetic upregulation of PGK1. Targeting this pathway through H4K12lac inhibitors such as Elbasvir thus emerges as a viable therapeutic approach for OC.

Female↗

PubMed2025

EIF2B5 promotes malignant progression of hepatocellular carcinoma by activating the PI3K/AKT signaling pathway through targeting RPL6.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options and poor prognosis. In this study, we demonstrated the critical role of EIF2B5 in driving HCC progression. We found EIF2B5 expression is significantly upregulated in HCC tumor tissues in several bioinformatics datasets, including The Cancer Genome Atlas, and that high expression of EIF2B5 predicts poor prognosis for HCC patients. Through a series of in vitro cell biology experiments, we found that EIF2B5 knockdown significantly attenuated Hep3B and HepG2 proliferation, migration, and invasion and increased cell cycle arrest, whereas EIF2B5 overexpression promoted HCC progression. Through mass spectrometry and immunoprecipitation validation, we found that EIF2B5 directly interacted with RPL6 and that when EIF2B5 was overexpressed in HCC cells, it promoted the expression of the downstream protein RPL6, which was able to activate the phosphatidylinositol kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) pathway and thereby increase the proliferation and invasion ability of HCC cell lines, as verified by second-generation sequencing analysis and western blot. We further verified these findings using the mouse ectopic tumor assay, and the results showed that EIF2B5 knockdown significantly inhibited tumor progression in HCC mice. The present study suggests that EIF2B5 promotes malignant progression of HCC by interacting with RPL6 and activating the PI3K/AKT/mTOR signaling pathway and may serve as a potential target for the treatment of HCC.

Humans↗

PubMed2025

Identification of ECE2 signaling in promoting non-small lung cancer progression through ET1/YAP1/MAGEA3 axis.

Non-small cell lung cancer (NSCLC) is a major cause of cancer-related mortality worldwide with high heterogeneity. However, the molecular basis for NSCLC development remains poorly understood. In this study, we analyzed endothelin converting enzyme 2 (ECE2) expression in NSCLC using transcriptome data from 59 normal and 515 NSCLC tissues obtained from The cancer genome atlas (TCGA) database. Additionally, we investigated the role of ECE2 in metastasis using 30 clinical NSCLC specimens. In vitro cell proliferation and migration assays were conducted using CCK8 and Transwell assays in NSCLC cells overexpressing ECE2. We employed Western blotting and immunostaining to assess activation of the endothelin-1 (ET1)/YAP1/MAGEA3 pathway. Furthermore, in vivo studies using subcutaneous xenograft mouse models with vector and ECE2-overexpressing A549 cells evaluated the anticancer effects. Our findings revealed elevated ECE2 expression in NSCLC tissues associated with poor prognosis. Moreover, overexpression of ECE2 enhanced both the proliferative and metastatic potential of NSCLC cells. Mechanistically, ECE2 promoted the production of ET1 in NSCLC cells. Subsequently, increased ET1 levels activated the YAP1/MAGEA3 pathway, thereby facilitating tumor progression. Our study uncovered the oncogenic role of ECE2 in promoting NSCLC growth through the ET1/YAP1/MAGEA3 pathway. Inhibiting ET1 signaling markedly enhanced the anticancer effectiveness of paclitaxel (PTX), providing a promising approach for managing NSCLC.

Humans↗

PubMed2026

A novel peptide encoded by circTLL1 drives osimertinib resistance in lung cancer by modulating the NT5C2/Ras/PI3K axis.

BACKGROUND: Acquired resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, remains a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). Although circular RNAs (circRNAs) have been increasingly implicated in drug resistance, most studies have focused on their canonical role as microRNA sponges, while their capacity to encode functional micropeptides remains largely unexplored. This study aimed to identify novel circRNAs involved in osimertinib resistance and to characterize their regulatory functions at the protein level. METHODS: Osimertinib-resistant (OR) NSCLC cell lines were established and validated. High-throughput RNA sequencing was performed to compare the circRNA expression profiles between parental and OR cells. The function of the candidate circRNA was assessed through a series of in vitro and in vivo experiments, including cell viability assays, apoptosis analysis, and xenograft mouse models. Mechanistic investigations involved mass spectrometry, co-immunoprecipitation and western blotting to explore its protein-coding potential and downstream signaling pathways. RESULTS: We identified a novel circRNA, termed circTLL1, that was stably and significantly upregulated in OR-NSCLC cells. Functionally, overexpression of circTLL1 promoted osimertinib resistance, whereas its knockdown restored drug sensitivity both in vitro and in vivo. Mechanistically, we discovered that circTLL1 harbors an open reading frame (ORF) that is translated into a novel 90-amino-acid protein, which we designated circTLL1-90aa. Further investigation revealed that circTLL1-90aa directly interacts with and promotes the degradation of 5'-nucleotidase, cytosolic II (NT5C2), thereby uncoupling nucleotide metabolism from its normal regulatory constraints. The consequent downregulation of NT5C2 leads to elevated GTP levels and leading to the sustained activation of the downstream Ras/PI3K/AKT signaling pathway. CONCLUSION: Our findings unveil a previously unrecognized circRNA/micropeptide/metabolism cascade underlying osimertinib resistance. The identification of the circTLL1-90aa/NT5C2/Ras/PI3K axis not only expands the functional repertoire of the non-coding genome but also provides new insights into the complexity of drug resistance. Given its selective upregulation in resistant cells, circTLL1-90aa holds promise both as a predictive biomarker for treatment stratification and as an actionable therapeutic target, offering a novel strategy to overcome osimertinib resistance in NSCLC patients.

Pyrimidines↗