Aug 2026· Oncology Research· Vol 34, pp. 1-10· 0 citations· 33 references
Medicine
TL;DR
Investigating the expression characteristics and biological functions of PSMB9 in colorectal cancer and the molecular pathways underlying its role in colorectal cancer initiation and progression finds that PSMB9 promotes the malignant progression of colorectal cancer by regulating the PI3K/Akt signaling pathway.
Abstract
Background: As a core component of the immunoproteasome, the β1i subunit (proteasome 20S subunit beta 9, PSMB9) is involved in antigen processing and presentation and regulates anti-tumor immune responses. PSMB9 is aberrantly overexpressed in colorectal cancer. However, the precise mechanisms through which PSMB9 contributes to the initiation, progression, and immune regulation of colorectal cancer remain unclear. This study aims to investigate the expression characteristics and biological functions of PSMB9 in colorectal cancer, and to further elucidate the molecular pathways underlying its role in colorectal cancer initiation and progression. The findings are expected to provide a theoretical basis for the development of targeted therapeutic strategies against colorectal cancer. Methods: PSMB9 expression in colorectal cancer was analyzed using the TCGA, GEO, GEPIA, and HPA databases, and further validated in normal colonic epithelial cells and colorectal cancer cell lines by RT-qPCR and Western blot. Lentiviral transduction was used to establish stably transduced HCT116 and SW480 cell lines with PSMB9 knockdown and overexpression, respectively. Cell proliferation, migration, and invasion were assessed by CCK-8, colony formation, wound healing, and Transwell assays. Key proteins of the PI3K/Akt signaling pathway were detected by Western blot. Results: PSMB9 was significantly upregulated at both the mRNA and protein levels in colorectal cancer tissues and cell lines. PSMB9 knockdown significantly inhibited the proliferation, migration, and invasion of colorectal cancer cells, while overexpression enhanced these malignant phenotypes. Mechanistically, PSMB9 exerted oncogenic effects through activation of the PI3K/Akt signaling pathway. Conclusions: PSMB9 promotes the malignant progression of colorectal cancer by regulating the PI3K/Akt signaling pathway.
BACKGROUND
Extensive clinical evidence has identified metastasis-associated colon cancer 1 (MACC1) as a pivotal cancer-promoting gene that actively fuels the advancement of neoplasms. However, the upstream transcriptional regulators of MACC1 and the specific posttranscriptional mechanisms involving N6-methyladenosine (m6A) modification that govern its expression remain largely undefined. This study aims to elucidate the regulatory network controlling MACC1 expression and its impact on colorectal cancer (CRC) progression.
METHODS
MACC1 expression and its potential regulators were systematically analyzed using public databases, including GEPIA, TCGA, and TIMER2, alongside clinical tissue samples and cell lines (SW480, HCT-116, and SW620). Functional experiments were conducted to assess cell viability, proliferation, invasion, and ferroptosis. These methodological approaches encompassed chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), as well as dual-luciferase reporter systems. Furthermore, in vivo validation was performed using a nude mouse xenograft model.
RESULTS
MACC1 was significantly upregulated in CRC tissues and cell lines, and its high expression correlated with an unfavorable prognosis. Functional assays revealed that silencing MACC1 inhibited CRC cell proliferation and invasion while inducing ferroptosis. Mechanistically, RNA binding protein 15 (RBM15) was identified as a key m6A methyltransferase component that stabilized MACC1 mRNA in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)- dependent manner. Furthermore, zinc finger and BTB domain-containing 33 (ZBTB33) was found to transcriptionally activate RBM15 by binding to its promoter region. Knockdown of RBM15 inhibited CRC cell invasion and proliferation and induced ferroptosis; these effects were notably reversed by MACC1 overexpression. Moreover, ZBTB33 silencing inhibited the key malignant phenotypes of CRC cells and induced ferroptosis by regulating RBM15. Further, RBM15 depletion suppressed tumor growth, which was attenuated by the restoration of MACC1.
DISCUSSION
Our study unveils a novel ZBTB33/RBM15/MACC1 signaling axis that drives CRC progression. Clinically, these findings not only deepen the understanding of m6A-mediated posttranscriptional regulation in CRC but also identify this axis as a promising therapeutic target for overcoming ferroptosis resistance and improving patient outcomes.
CONCLUSION
These findings uncover a novel ZBTB33/RBM15/MACC1 regulatory axis in CRC, where ZBTB33 transcriptionally activates RBM15 to enhance MACC1 mRNA stability, ultimately suppressing ferroptosis and promoting tumor progression.
Lichun Wang, Bin Guo, Xueping Jiao et al.· Current Gene Therapy· 0 citations
: Background: Rho GTPase-activating protein 40 (ARHGAP40), downregulated in various tumors, including basal cell carcinoma, has an unclear role in colorectal cancer (CRC). This study aimed to elucidate the function and clinical significance of ARHGAP40 in CRC. Methods: ARHGAP40 expression in CRC tissues was evaluated by immunohistochemistry and analyzed in relation to clinicopathological features and patient survival. Gain-and loss-of-function experiments were performed in CRC cell lines to assess cell proliferation, apoptosis, migration, and invasion. RNA sequencing, co-immunoprecipitation, Ras homolog gene family member A (RhoA) activation assays, and rescue experiments were conducted to explore the underlying mechanism. Results: ARHGAP40 expression was significantly decreased in CRC tissues and cell lines. Low ARHGAP40 expression was associated with poor differentiation ( p < 0.001), deeper tumor invasion ( p = 0.004), lymph node metastasis ( p < 0.001), advanced TNM stage ( p < 0.001), and unfavorable prognosis in patients with CRC ( p < 0.05). Functional experiments showed that ARHGAP40 overexpression suppressed CRC cell proliferation, migration, and invasion, while promoting apoptosis, whereas ARHGAP40 knockdown exerted opposite effects. Mechanistically, ARHGAP40 interacted with RhoA and negatively regulated its activation. Moreover, restoration of RhoA activity partially reversed the effects of ARHGAP40 overexpression on CRC cell proliferation and apoptosis. Conclusions: ARHGAP40 is downregulated in CRC, and its loss may contribute to tumor progression, possibly through dysregulation of RhoA activity.
Bin Lian, Na You, Jing-Yun Wang et al.· Biocell (Mendoza)· 0 citations
BACKGROUND
Methyltransferase-like 7B (METTL7B) is a Golgi-associated methyltransferase linked to malignant progression of multiple tumors. However, its specific role and underlying mechanisms in gastric cancer remain unclear.
METHODS
METTL7B expression and its clinicopathological and prognostic significance in gastric cancer were assessed using bioinformatics and immunohistochemistry. Functional roles (proliferation, migration, and invasion) were evaluated using in vitro assays. Underlying mechanisms were explored via bioinformatics enrichment analysis and Western blotting.
RESULTS
METTL7B expression was significantly upregulated in gastric cancer tissues and correlated with poor prognosis. Knockdown of METTL7B inhibited the proliferation, migration, and invasion of gastric cancer cells. Mechanistically, knockdown of METTL7B suppressed the PI3K/Akt signaling pathway.
CONCLUSIONS
METTL7B is crucial in promoting gastric cancer progression via the PI3K/Akt signaling pathway, suggesting its potential as a prognostic biomarker and therapeutic target in gastric cancer.
Tao Wang, Beibei Ge, Chang Liu et al.· Gene· 0 citations
ETV4 (ETS-transformation-specific variant 4) is a member of the ETS transcription factor family that has been extensively studied for its oncogenic functions in cancers. Here, we summarize the role and mechanisms of ETV4 in cancer biology, with a particular focus on colorectal cancer (CRC), as well as its biomarkers and therapeutic potential. As a transcription factor, ETV4 regulates the expression of target genes by recognizing the GGA(A/T) core conserved sequence. It is frequently overexpressed in pan-cancer, where its overexpression associated with poor prognosis. Upon activation by oncogenic signaling pathways (e.g., MAPK, PI3K/Akt, and WNT), ETV4 transcriptionally regulates downstream genes to promote tumor cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), chemoresistance, metabolic reprogramming, and immune evasion. It also form a vicious positive feedback loop that continuously activates oncogenic signaling. In CRC, ETV4 is overexpressed, correlating with advanced disease, lymph node metastasis, and poor prognosis. Upon activation by oncogenic signals, ETV4 directly activate target genes (such as matrix metalloproteinases) to mediate adenoma-to-adenocarcinoma progression, proliferation, EMT, ferroptosis, invasion, metastasis, metabolic reprogramming, and tumor microenvironment remodeling in CRC. ETV4 also forms transcriptional complexes with certain epigenetic factors, such as miRNAs and p300. Moreover, ETV4 is a promising biomarker for CRC diagnosis, prognosis, and adenoma-to-adenocarcinoma progression. Targeting ETV4 or its upstream pathways represents a potential therapeutic strategy for CRC. However, there are still many unresolved issues in current research. For example, the role of ETV4 in immune evasion and tumor microenvironment remodeling remains at the descriptive stage, and the specific mechanisms by which it regulates immune cell recruitment have not yet been elucidated. Future efforts include utilizing multi-omics approaches to elucidate the mechanisms by which ETV4 shapes the CRC microenvironment and exploring the application prospects in tumor immunotherapy.
Yuanbin Liu, Yiyun Wang, Ming Huang et al.· Frontiers in Oncology· 0 citations
BACKGROUND
Colorectal cancer (CRC) is the third most common gastrointestinal cancer in terms of morbidity and mortality worldwide. Reprogramming of glucose metabolism will directly affect the energy supply pattern of tumor cells and determine their malignant biological behavior. Mitofusin-2 (MFN2) has been shown to be associated with glycolysis. Therefore, targeting MFN2 may be a potential therapeutic approach for CRC.
METHODS
Firstly, GSE143939, GSE81558 dataset and GSE184093 dataset were used to screen differentially expressed mRNAs in CRC. The expression of MFN2 in colorectal cancer was detected by TCGA website, Immunohistochemistry and western blot analysis. The impacts of MFN2 on CRC malignant biological behavior were evaluated by a series of in vitro assays. The potential molecular mechanism of MFN2 was elucidated by co-immunoprecipitation, immunofluorescence staining, western blotting and rescue experiment. The effect of MFN2 on tumor growth capacity was assessed in xenograft model.
RESULTS
TCGA and GEO data analysis showed that MFN2 was differentially expressed in CRC, which was significantly lowly expressed in CRC cell lines and tissues. Aberrant expression of MFN2 could reduce glycolysis of CRC cells in vitro and subsequently activate apoptosis and hinder proliferation and migration in vitro. In vivo, MFN2 overexpression retarded tumor growth rate. Mechanistically, MFN2 interacted with PFKP and facilitated the binding of TRIM21 to PFKP to mediate its degradation, thereby hindering the malignant progression of CRC.
CONCLUSIONS
Overexpression of MFN2 suppressed CRC cell glycolysis and tumor growth by enhancing TRIM21-mediated degradation of PFKP. Targeting the MFN2/TRIM21/PFKP axis may serve as a new direction for CRC treatment.
Huiyuan Jiang, Hongwei Guo, Yan Wang et al.· Molecular Immunology· 0 citations
BACKGROUND
Our previous bioinformatic study identified Collagen type I alpha 1 chain (COL1A1) as a candidate regulator associated with gastric cancer (GC) progression and response to anti-angiogenic therapy. However, whether COL1A1 influences the sensitivity of GC cells to apatinib and the underlying mechanisms remains unclear.
METHODS
Multiple bioinformatics platforms were used to investigate the correlation between COL1A1 expression and GC progression and prognosis. Gain- and loss-of-function assays were conducted in GC cell lines to validate the regulatory role of COL1A1 in apatinib sensitivity. Functional validation included a series of in vitro and in vivo studies. Protein expression profiling was further performed to quantify key proteins involved in glycolytic and angiogenic signaling pathways.
RESULTS
High COL1A1 expression was associated with tumor progression and poor prognosis in GC patients. Knockdown of COL1A1 enhanced the sensitivity of MKN-74 cells to apatinib and weakened their proliferative, migratory, invasive, and colony-forming abilities in vitro, as well as tumor growth and metastasis in vivo. Overexpression of COL1A1 in SNU-1 cells had the opposite effects. Mechanistically, COL1A1 modulated glycolytic reprogramming and profoundly affected the angiogenic potential of GC cells, uncovering its role in driving therapeutic evasion.
CONCLUSION
COL1A1 may contribute to reduced apatinib sensitivity in GC cells, at least partly by enhancing glycolytic metabolism and angiogenic activity. These findings suggest that COL1A1 is a potential regulator worthy of further investigation for improving the therapeutic response to apatinib in GC.
