Thyroid carcinoma (TC), the most prevalent endocrine malignancy, accounts for 3-4% of global cancer cases and continues to increase in incidence worldwide. Despite advances in diagnosis and treatment, a subset of thyroid cancers remains clinically incurable, underscoring the urgent need to elucidate molecular pathogenesis and identify novel therapeutic targets. Here, we identify complement factor I (CFI) as a key downstream effector of Retinoic acid receptor gamma (RARγ). Mechanistically, RARγ transcriptionally upregulates CFI expression, and analyses of clinical TC specimens demonstrated a strong correlation between RARγ and CFI expression. Conditioned media from RARγ-overexpressing TC cells induced M2-like polarisation of THP-1-derived macrophage-like cells, as evidenced by increased CD206 expression and elevated IL-10 levels-effects that were abolished by CFI neutralisation. In xenograft models, RARγ/CFI-mediated TAM reprogramming drove tumour progression, with RARγ-knockdown tumours exhibiting reduced volumes via macrophage-dependent mechanisms. Importantly, CFI did not affect TC cell-autonomous proliferation, suggesting that its pro-tumoural effects are mediated by the TME rather than directly on tumour cells. Collectively, Our findings establish RARγ/CFI signalling as a microenvironmental rheostat controlling TAM polarisation and provide new insights into the immunobiology of thyroid cancers.

8511 Background: Elisrasib (D3S-001) is a next-generation KRAS G12C inhibitor (G12Ci) designed to improve target engagement (TE) efficiency and overcome growth factor-induced nucleotide exchange. This unique MoA distinguishes elisrasib from prior G12Ci and has demonstrated robust and durable anti-tumor activity in PDX models, and in combination with immunotherapy (IO) in immunocompetent models. Current ongoing phase 1/2 trial (NCT05410145) evaluates elisrasib as monotherapy (mono) or combination (combo) with pembrolizumab as first line (1L) therapy for advanced NSCLC harboring G12C mutation. Methods: Treatment naïve patients (pts) with G12C mutant advanced stage NSCLC were eligible. Elisrasib is administered 600mg QD orally in a 21-day cycle as mono or combo with pembrolizumab i.v. 200mg Q3W. The key objectives included safety and efficacy. ctDNA dynamic was analyzed by Guardant360 CDx or OncoCompass Target panels. Results: As of 06 Jan 2026, 43 pts and 52 pts received mono and combo. Median study follow up was 8.5m and 5.7m in mono and combo, respectively. In mono, 41 (PD-L1 TPS [22C3]: 21 <1% and 20 ≥1%) out of 43 pts were efficacy evaluable. Overall ORR was 78.0% (32/41). Subgroup ORRs in TPS <1% and ≥1% were 76.2% and 80.0%, respectively. Median PFS and DOR were immature. 6m PFS rate was 68.9% and 6m DOR rate was 77.2%. Above results provide first time evidence of G12Ci monotherapy in 1L NSCLC. In combo, 48 (PD-L1 TPS [22C3]: 17 <1%, 11 1-49%, and 20 ≥50%) out of 52 pts were efficacy evaluable. Overall ORR was 81.2% (39/48). Subgroup ORRs in TPS <1%, 1-49%, and ≥50% were 70.6%, 72.7% and 95.0%, respectively. Median PFS and DOR in the overall combo population were immature. 6m PFS rate was 74.6% and 6m DOR rate was 80.5%. Toxicity profile is summarized in Table. Baseline ctDNA G12C+ was detected in 90% (37/41) of mono and 80% (37/46) of combo. 35 mono and 25 combo pts completed on-treatment ctDNA analysis, with 83% and 100% achieved molecular response (≥90% G12C MAF reduction), respectively. PK at 600mg QD achieved C trough exposure of ~5nM and ~3nM with mono and combo, respectively, with overlapping variabilities at steady state, both well above the required exposure (1nM) for complete TE. Conclusions: Both elisrasib monotherapy and in combination with pembrolizumab show strong efficacy and good tolerability as 1L treatments for G12C-mutant NSCLC, warrant for randomized study to evaluate elisrasib as a potential new standard of care. Clinical trial information: NCT05410145 . TRAEs* 1L NSCLC Mono (N=43) 1L NSCLC Combo (N=52) Any Grade 41 (95.3%) 48 (92.3%) ≥G3 3 (7.0%) 17 (32.7%) LFT TRAEs* by PT (≥G3) ALT increased 0 4 (7.7%) AST increased 0 3 (5.8%) *TRAEs for combo cohort is related to elisrasib and/or pembrolizumab.

Although ultrasound therapy is efficacious and safe in clinical oncology, its capacity to elicit an anti-tumor immune response is constrained by ultrasound-induced apoptosis. Pyroptosis, which releases immunogenic damage-associated molecular patterns (DAMPs), can significantly enhance immune activation. It necessitates robust Gasdermin E (GSDME) expression in cancer cells for caspase-3-mediated pyroptosis. An epigenetic strategy is introduced to induce cancer pyroptosis during sonotherapy using a nanocoordinator (HTA) constructed through metal-phenolic coordination involving Aza (a DNA methyltransferase inhibitor), TiO2 nanoparticles, and polyphenol-modified hyaluronic acid. While Aza restores GSDME expression, TiO2 generates reactive oxygen species (ROS) under ultrasound stimulation, activating caspase-3 and inducing pyroptosis via GSDME cleavage. In an orthotopic breast cancer model, HTA enhanced anti-tumor immunity and improved the efficacy of sonodynamic therapy (SDT). This approach presents a novel strategy for augmenting SDT through epigenetically induced pyroptosis.

Radiation therapy (RT) is a prevalent cancer treatment; however, its therapeutic outcomes are frequently impeded by tumor radioresistance, largely attributed to metabolic reprogramming characterized by increased fatty acid uptake and oxidation. To overcome this limitation, we developed polyphenol-metal coordination polymer (PPWQ), a novel nanoradiotherapy sensitizer specifically designed to regulate fatty acid metabolism and improve RT efficacy. These nanoparticles (NPs) utilize a metal-phenolic network (MPN) to integrate tungsten ions (W6+), quercetin (QR), and a PD-L1-blocking peptide within a PEG-polyphenol scaffold. When exposed to X-rays, PPWQ induces reactive oxygen species (ROS) to cause DNA damage, while QR inhibits CD36 expression, effectively curbing fatty acid uptake and mitigating immune evasion. In a 4T1 tumor-bearing mouse model, PPWQ demonstrated significant enhancement of RT by facilitating dendritic cell activation, boosting memory cytotoxic T lymphocytes, and skewing macrophages toward a pro-immune phenotype. These results underscore the potential of PPWQ to target metabolic vulnerabilities and advance the integration of immunotherapy with radiotherapy.

GRWD1, a novel WD40-repeat-containing protein designated glutamate-rich WD repeat, is highly expressed in CRC and participates in a series of oncogenic activities. However, the cause of GRWD1 overexpression and its oncogenic mechanism in CRC remains elusive. This study revealed that GRWD1 was correlated with inflammation and was progressively upregulated during the progression of Azoxymethane/Dextran sodium sulfate (AOM/DSS) in a mouse model. Moreover, GRWD1 was activated by the IL-6/STAT3 signal pathway in CRC cells. Besides, it promoted the degradation of p53 and further induced GLUT1 to facilitate aerobic glycolysis in CRC. Taken together, GRWD1 played an oncogenic role in tumorigenesis of CRC and represented a promising therapeutic target.

Resistance mechanisms to first-generation (1G) KRAS G12C inhibitors (G12Ci) are diverse, with previous data revealing a heterogeneous pattern characterized by multiple subclonal events emerging after treatment (Tx). Incomplete G12C target engagement (TE) and G12Ci induced G12C amplification contributed to the resistance mechanisms against 1G G12Ci. D3S-001, a next-generation KRAS G12Ci, has demonstrated potent, faster and complete TE to effectively deplete active KRAS mutated protein. In pre-clinical studies, D3S-001 resulted in tumor regression in xenograft models that are resistant to sotorasib (soto) and adagrasib (ada). Phase 1 results demonstrated favorable safety and promising early efficacy across NSCLC, CRC and PDAC; Here, we present findings in G12Ci resistant NSCLC patients (pts) from the ongoing Phase 2 trial (NCT05410145). Pts of locally advanced or metastatic NSCLC with historically confirmed KRAS G12C mutation were eligible for inclusion if they had radiologically or clinically documented PD following TX of 1 prior KRAS G12Ci achieving CR/PR or SD for >= 6 months. In this cohort, D3S-001 was administered as monotherapy at 600mg once daily. The key objectives included safety, efficacy, and ctDNA kinetics by liquid biopsy. As of 14 Feb 2024, a total of 20 pts were enrolled. Prior G12Ci Tx included FDA approved and experimental G12Cis. 7 pts had soto, 1 pt had ada and 12 pts had other experimental G12Cis. During their prior G12Ci Tx, 8 pts (40%) achieved PR, 7 pts (35%) achieved SD, and 5 pts (25%) were unknown as the BOR. 14 pts (70%) were enrolled into this study immediately after PD from prior G12Ci. Median study follow-up was 4.7 months (range: 1.3-12.8 months), and 9 pts (45%) remain on-study Tx. TRAE of any grade occurred in 18 pts (90%). Of which, 2 (10%) were Grade 3 (no >=G4). PR was achieved in 6 pts (30%). Median DOR was 8.2 months. DCR was 80% and tumor shrinkage was observed in 12 of the 20 (60%) pts. Of the 20 pts, 14 (70%) were KRAS G12C ctDNA positive at baseline [bG12C(+)]. Notable baseline co-mutations included secondary KRAS alterations (A146V, R68S and three G12C amplification), BRAF, EGFR, NTRK1/2/3, TP53, etc. Of the 14 bG12C(+) pts, 11 achieved >90% G12C MAF reduction including 8 with complete clearance. All 6 radiological responders were bG12C(+) and 5 of 6 had complete clearance of G12C MAF. Remarkably, of the 3 pts with KRAS amplification, 2 achieved PR and 1 SD with D3S-001 Tx. Conversely, pts who had immediate PD to D3S-001 carried baseline gene alterations of switch II pocket mutation (KRAS R68S), BRAF V600E, MYC amplification, NTRK2, CDKN2A and PIK3CG. These findings align with preclinical observation that D3S-001 was effective in G12Ci resistant xenograft model including those with KRAS G12C gene amplification. These findings highlight the potential of D3S-001 to overcome the limitations of earlier KRAS G12Ci and address unmet needs in G12Ci resistant NSCLC, offering a promising therapeutic option for pts with KRAS G12C-mutant cancers. Herbert H. Loong, Ziming Li, Byoung Chul Cho, Jun Zhao, John Park, Zhengbo Song, Bowyer Samantha, Ki Hyeong Lee, Xiaorong Dong, Jianya Zhou, Cheng Chen, Yangbo Liu, Yandong Shen, Shaonan Wang, Zifei Fan, Qian Chen, Hui Wang, Jing Zhang, Zhi Jian Chen, Tony S. Mok, Shun Lu. D3S-001, a next generation GDP-bound KRAS G12C inhibitor, as monotherapy in KRAS G12C inhibitor resistant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT266.

Colorectal cancer (CRC) ranks as the third most frequently diagnosed cancer and is the second leading cause of cancer-related deaths globally. Recently, RNA-binding protein 39(RBM39), a critical factor in tumor-targeted mRNA and protein expression, has played a vital role in tumorigenesis and has broad development prospects in clinical treatment and drug research. However, the functional roles of RBM39 in the progression of CRC remain largely unexplored. This study found that RBM39 is notably overexpressed at both the mRNA and protein levels in CRC tissues compared with normal adjacent tissues. RBM39 was identified as a potential therapeutic target for colorectal cancer. Elevated RBM39 mRNA levels in CRC patients indicated worse survival probabilities. We show that RBM39 enhances the proliferation, migration, and invasion ability of CRC cells. Furthermore, we have made an innovative discovery that increased RBM39 inhibits apoptosis in CRC cells. Mechanistically, RNA-seq analysis indicated that RBM39 activates the NF-κB pathway, which plays a pivotal role in driving the malignant biological behaviors of colorectal cancer. Notably, these findings represent a novel contribution to our understanding of the mechanistic underpinnings of CRC, as they have not been previously documented in the literature. In the in vivo nude mouse xenograft model, our study demonstrates that the targeted knockdown of RBM39 markedly suppresses tumor formation, highlighting a novel therapeutic strategy for combating colorectal cancer. In conclusion, RBM39 emerges as a promising candidate for clinical diagnosis and targeted treatment of colorectal cancer, with implications for future research in tumor biology and therapeutic strategies.

Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.

We previously demonstrated a positive relation of secretory phospholipase A2 group IIA (sPLA2-IIA) with circulating high-density lipoprotein cholesterol (HDL-C) in patients with coronary artery disease, and sPLA2-IIA increased cholesterol efflux in THP-1 cells through peroxisome proliferator-activated receptor-γ (PPAR-γ)/liver X receptor α/ATP-binding cassette transporter A1 (ABCA1) signaling pathway. The aim of the present study was to examine the role of sPLA2-IIA over-expression on lipid profile in a transgenic mouse model. Fifteen apoE-/- and C57BL/7 female mice received bone marrow transplantation from transgenic SPLA2-IIA mice, and treated with specific PPAR-γ inhibitor GW9662. High fat diet was given after one week of bone marrow transplantation, and animals were sacrificed after twelve weeks. Immunohistochemical staining showed over-expression of sPLA2-IIA protein in the lung and spleen. The circulating level of HDL-C, but not that of low-density lipoprotein cholesterol (LDL-C), total cholesterol, or total triglyceride, was increased by sPLA2-IIA over-expression, and was subsequently reversed by GW9662 treatment. Over-expression of sPLA2-IIA resulted in augmented expression of cholesterol transporter ABCA1 at mRNA level in the aortas, and at protein level in macrophages, co-localized with macrophage specific antigen CD68. GW9662 exerted potent inhibitory effects on sPLA2-IIA-induced ABCA1 expression. Conclusively, we demonstrated the effects of sPLA2-IIA on circulating HDL-C level and the expression of ABCA1, possibly through regulation of PPAR-γ signaling in transgenic mouse model, that is in concert with the conditions in patients with coronary artery disease.

BackgroundHuman tumors pose significant challenges, with targeted therapy against specific molecular targets or signaling pathways being a mainstay alongside surgical resection. Previous studies have implicated KHDRBS1 in the oncogenesis of certain human tumors such as colorectal and prostate cancers, underscoring its potential as a therapeutic target. However, the comprehensive expression pattern of KHDRBS1 in hepatocellular carcinoma (HCC) warrants further exploration.MethodsIntegrating and analyzing multi-omics, multi-cohort data from public databases, coupled with clinical samples and molecular biology validation, we elucidate the oncogenic role of KHDRBS1 in HCC progression. Additionally, leveraging HCC single-cell sequencing data, we segregate malignant cells into KHDRBS1-positive and negative subsets, uncovering significant differences in their expression profiles and functional roles.ResultsOur study identifies KHDRBS1 as a tumor-promoting factor in HCC, with its positivity correlating with tumor progression. Furthermore, we highlight the clinical significance of KHDRBS1-positive malignant cells, aiming to further propel its clinical utility.ConclusionKHDRBS1 plays a key role in HCC development. This study provides crucial insights for further investigation into KHDRBS1 as a therapeutic target in HCC.

Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation -dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/ Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.

OBJECTIVE:The tumor microenvironment (TME) in cholangiocarcinoma (CHOL) is typically characterized by a low level of immune infiltration, which accounts for the dismal prognosis of this patient population. This study sought to investigate the mechanisms underlying the reduced infiltration of immune cells into the CHOL TME.METHODS:We constructed a Least Absolute Shrinkage and Selection Operator (LASSO) regression model to identify prognosis-related differentially expressed genes (DEGs). The 'Corrplot' package was employed to analyze the correlation between dermatopontin (DPT) and immune infiltration in CHOL. The Tumor and Immune System Interaction Database (TISIDB) was used to evaluate the association between DPT and immunology. Single-cell analysis was conducted to localize CCL19 secretions. Western blot and qPCR were utilized to detect DPT expression, while immunofluorescence was performed to investigate the cellular localization of DPT. Additionally, ELISA analysis was employed to assess the alteration in CCL19 secretion in cancer-associated fibroblasts (CAFs) and macrophages.RESULTS:Our findings revealed that CHOL patients with low DPT expression had a poorer prognosis. Enrichment analysis demonstrated a positive correlation between DPT levels and the infiltration of immunomodulators and immune cells. Moreover, high DPT levels were associated with enhanced anti-PD-1/PD-L1 immunotherapeutic responses. Furthermore, DPT expression impacted the landscape of gene mutations, showing a negative association with tumor grade, stage, and lymph node metastasis. Based on the results of protein peptides analysis and cell experiments, it was inferred that the downregulation of DPT in CHOL cells effectively suppressed the secretion of CCL19 in macrophages.CONCLUSIONS:DPT is a novel prognosis-related biomarker for CHOL patients, and this study provides preliminary insights into the mechanism by which DPT promotes the infiltration of immune cells into the CHOL TME.

Cholangiocarcinoma (CCA) is a primary malignant tumor of the liver, typically diagnosed in advanced stages. Surgical resection remains the principal treatment method in clinical practice. Regrettably, the majority of patients receive their diagnosis at an advanced stage, making surgical intervention unfeasible. While chemotherapy serves as the main palliative treatment for advanced CCA, its effectiveness is significantly limited due to the rapid development of chemoresistance. Studying the pathogenesis of CCA and new resistance targets is crucial for improving clinical outcomes. In our current study, we first identified the expression of SLC16A1 in the transcriptome and proteome of human tumors and found abnormal expression of SLC16A1 in various human cancers. Subsequently, we focused our attention on the role of SLC16A1 in CCA. Utilizing bioinformatics analysis, we pioneered the identification of the clinical significance of SLC16A1 in this type of cancer. Specifically, higher expression levels of SLC16A1 were observed in CCA patients with venous invasion and higher T and M stages. Additionally, patients with higher SLC16A1 expression had poorer prognoses. These results suggest the oncogenic role of SLC16A1 in CCA. Further immune infiltration analysis revealed a significant correlation between SLC16A1 and the infiltration levels of cells like neutrophils and macrophages in the tumor microenvironment, indicating SLC16A1's potential involvement in regulating the tumor immune microenvironment of CCA. Moreover, results from functional and pathway enrichment analyses revealed that SLC16A1 might affect clinical outcomes in CCA patients by participating in drug metabolism processes. Finally, through further in vitro and in vivo experiments, we confirmed that SLC16A1, as an oncogene in CCA, promotes the growth of CCA cells and chemoresistance. Knocking down SLC16A1 inhibited the growth of CCA cells and enhanced their sensitivity to 5-Fluorouracil (5-FU). Overall, this study reveals the key role of SLC16A1 in the development of CCA and highlights its significance as a potential target for improving treatment efficacy and chemotherapy sensitivity.

Preadipocyte determination expanding the pool of preadipocytes is a vital process in adipocyte hyperplasia, but the molecular mechanisms underlying this process are yet to be elucidated. Herein, SRY-related HMG box transcription factor 4 (SOX4) was identified as a critical target in response to BMP4- and TGFβ-regulated preadipocyte determination. SOX4 deficiency is sufficient to promote preadipocyte determination in mesenchymal stem cells (MSCs) and acquisition of preadipocyte properties in nonadipogenic lineages, while its overexpression impairs the adipogenic capacity of preadipocytes and converts them into nonadipogenic lineages. Mechanism studies indicated that SOX4 activates and cooperates with LEF1 to retain the nuclear localization of β-catenin, thus mediating the crosstalk between TGFβ/BMP4 signaling pathway and Wnt signaling pathway to regulate the preadipocyte determination. In vivo studies demonstrated that SOX4 promotes the adipogenic-nonadipogenic conversion and suppresses the adipocyte hyperplasia. Together, our findings highlight the importance of SOX4 in regulating the adipocyte hyperplasia in obesity.

DPY30 belongs to the core subunit of components of the histone lysine methyltransferase complex, which is implicated in tumorigenesis, cell senescence, and other biological events. However, its contribution to colorectal carcinoma (CRC) progression and metastasis has yet to be elucidated. Therefore, this study aimed to investigate the biological function of DPY30 in CRC metastasis both in vitro and in vivo. Herein, our results revealed that DPY30 overexpression is significantly positively correlated with positive lymph nodes, epithelial-mesenchymal transition (EMT), and CRC metastasis. Moreover, DPY30 knockdown in HT29 and SW480 cells markedly decreased EMT progression, as well as the migratory and invasive abilities of CRC cells in vitro and lung tumor metastasis in vivo. Mechanistically, DPY30 increased histone H3K4me3 level and promoted EMT and CRC metastasis by upregulating the transcriptional expression of ZEB1. Taken together, our findings indicate that DPY30 may serve as a therapeutic target and prognostic marker for CRC.

Brf1 (TFIIB-related factor 1) is a transcription factor, which specifically modulates the transcription of RNA polymerase III-dependent genes (RNA Pol III genes), such as tRNAs and 5S rRNA. The products of tRNAs and 5S rRNA transcription will be changed with the alteration of Brf1 expression. Whereas deregulation of Brf1 and RNA Pol III genes are tightly associated with cell proliferation and transformation, and tumorigenesis. In recent years, emerging studies indicate that Brf1 expression is increased in patients with cancers. In this review, we summarize the progress of the abnormal expression of Brf1 in different human cancers to explore an underlying mechanism and its clinical implication, as well as to prompt its application prospect. With the depth of the Brf1 study and the progress of biotechnology, the status of Brf1 expression may be used as a universal indicator of the early detection and prognosis observation of human cancers.

DPY30, a core subunit of the SET1/MLL histone H3K4 methyltransferase complexes, plays an important role in diverse biological functions through the epigenetic regulation of gene transcription, especially in cancer development. However, its involvement in human colorectal carcinoma (CRC) has not been elucidated yet. Here we demonstrated that DPY30 was overexpressed in CRC tissues, and significantly associated with pathological grading, tumor size, TNM stage, and tumor location. Furthermore, DPY30 knockdown remarkably suppressed the CRC cell proliferation through downregulation of PCNA and Ki67 in vitro and in vivo, simultaneously induced cell cycle arrest at S phase by downregulating Cyclin A2. In the mechanistic study, RNA-Seq analysis revealed that enriched gene ontology of cell proliferation and cell growth was significantly affected. And ChIP result indicated that DPY30 knockdown inhibited H3 lysine 4 trimethylation (H3K4me3) and attenuated interactions between H3K4me3 with PCNA, Ki67 and cyclin A2 respectively, which led to the decrease of H3K4me3 establishment on their promoter regions. Taken together, our results demonstrate overexpression of DPY30 promotes CRC cell proliferation and cell cycle progression by facilitating the transcription of PCNA, Ki67 and cyclin A2 via mediating H3K4me3. It suggests that DPY30 may serve as a potential therapeutic molecular target for CRC.

The nuclear receptor superfamily RAR is generally considered to play a crucial role in the development of tumors by regulating the transcription of target genes. Nevertheless, whether RARγ performs tumor-promoting or tumor-suppressing functions and its specific mechanism in thyroid carcinoma (TC) remain unknown. Here, our study demonstrated that RARγ was abnormally overexpressed in TC tissues compared with normal thyroid tissues. Moreover, RARγ expression was remarkably correlated with cell phenotypes such as cell proliferation, migration and invasion. Mechanistically, RARγ knockdown effectively decreased the phosphorylation levels of JAK1 and STAT3, leading to decreased expression of the membrane protein CD24. In a coculture system, TC cells with high levels of CD24 in the membrane were more likely to escape phagocytosis by macrophages via the combination of CD24 with the inhibitory receptor Siglec-10 in the membrane of macrophages. In contrast, the ability of macrophages to engulf TC cells was notably elevated through exogenous addition of CD24 antibody. Collectively, our study revealed a previously undiscovered molecular mechanism of RARγ in promoting the development of TC, shedding light on RARγ as a promising therapeutic target for TC.

Osteoarthritis (OA) is a severe inflammation-related disease which leads to cartilage destruction. The retinoic acid receptor gamma (RARγ) has been indicated to be involved in many inflammation processes. However, the role and mechanism of RARγ in cartilage destruction caused by inflammation in OA are still unknown. Here, we demonstrated that the RARγ was highly expressed in chondrocytes of OA patients compared with healthy people and was positively correlated with the damage degree of cartilage in OA. Cytokine TNF-α promoted the transcription and expression of RARγ through activating the NF-κB pathway in OA cartilage. In addition, the overexpression of RARγ resulted in the upregulation of matrix degradation and inflammation associated genes and downregulation of differentiation and collagen production genes in human normal chondrocyte C28/I2 cells. Mechanistically, overexpression of RARγ could increase the level of p-IκBα and p-P65 to regulate the expression of downstream genes. RARγ and IκBα also could interact with each other and had the same localization in C28/I2 cells. Moreover, the SD rats OA model induced by monosodium iodoacetate indicated that CD437 (RARγ agonist) and TNF-α accelerated the OA progression, including more severe cartilage layer destruction, larger knee joint diameter, and higher serum ALP levels, while LY2955303 (RARγ inhibitor) showed the opposite result. RARγ was also highly expressed in OA group and even higher in TNF-α group. In conclusion, RARγ/NF-κB positive feedback loop was activated by TNF-α in chondrocyte to promote cartilage destruction. Our data not only propose a novel and precise molecular mechanism for OA disease but also provide a prospective strategy for the treatment.