CSNK2B contributes to colorectal cancer cell proliferation by activating the mTOR signaling.
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ABSTRACT:
SUBMITTER: Yu S
PROVIDER: S-EPMC8222461 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mitochondrial Pyruvate Carrier 1 (MPC1), one of the rate-limiting proteins involved in glycolysis metabolism, has been demonstrated as a tumor inhibitor in several cancers. This study was conducted with the aim of exploring the role and underlying mechanisms of MPC2 in colorectal cancer (CRC). Here, we found that MPC2 expression was decreased in CRC samples. According to the analysis on our TMA data, lower expression of MPC2 is correlated with a higher incidence of distant metastasis and lymph node invasion, bigger tumor size, low survival rate of patients, and advanced T stages. Functionally, in vivo/vitro experiments showed that MPC2 knockdown induced CRC cell proliferation and growth, while MPC2 overexpression inhibited the proliferation and growth of CRC. Further study demonstrated that MPC2 knockdown resulted in aerobic glycolysis in CRC cells. Similarly, MPC2 overexpression in CRC cells also caused inhibited aerobic glycolysis. Further study found that MPC2 knockdown in CRC cell lines activated the mTOR signaling pathway, and the addition of rapamycin reversed the promoting effect of MPC2 knockdown on CRC proliferation and glycolysis. Likewise, the addition of MHY1485 also reversed the MPC2 overexpression's role in hindering aerobic glycolysis in CRC cells. Collectively, our study established that low expression of MPC2 led to CRC growth as well as aerobic glycolysis through the regulation of the mTOR pathway in CRC cells, indicating a potential biomarker and therapy target for CRC.
| S-EPMC7984920 | biostudies-literature
Project description:Colorectal cancer (CRC) is the fourth most lethal cancer in the world. Heat shock protein 60 (HSP60), a mitochondrial chaperone that maintains mitochondrial proteostasis, is highly expressed in tumors compared with in paracancerous tissues, suggesting that high HSP60 expression benefits tumor growth. To determine the effects of HSP60 expression on tumor progression, stable HSP60-knockdown HCT116 cells were constructed in the present study, revealing that knockdown of HSP60 inhibited cell proliferation. Proteomic analysis demonstrated that mitochondrial proteins were downregulated, indicating that knockdown of HSP60 disrupted mitochondrial homeostasis. Metabolomic analysis demonstrated that cellular adenine levels were >30-fold higher in HSP60-knockdown cells than in control cells. It was further confirmed that elevated adenine activated the AMPK signaling pathway, which inhibited mTOR-regulated protein synthesis to slow down cell proliferation. Overall, the current results provide a valuable resource for understanding mitochondrial function in CRC, suggesting that HSP60 may be a potential target for CRC intervention.
| S-EPMC8258614 | biostudies-literature
Project description:The progression of CRC is a multistep process involving several genetic changes or epigenetic modifications. NDN is a member of the MAGE family, encoding a protein that generally suppresses cell proliferation and acting as a transcriptional repressor. Immunohistochemical staining revealed that the expression of NDN was significantly down-regulated in CRC tissues compared with normal tissues and the down-regulation of NDN in CRC could reflect the hypermethylation of the NDN promoter. Treatment of the CRC cell line SW480 with the demethylating agent 5-Aza-CdR restored the NDN expression level. The down-regulation of NDN was closely related to poor differentiation, advanced TNM stage and poor prognosis of CRC. The inhibition of NDN promoted CRC cell proliferation by enriching cells in the S phase. Furthermore, we observed that NDN binds to the GN box in the promoter of LRP6 to attenuate LRP6 transcription and inhibit the Wnt signaling pathway in CRC. In conclusion, our study revealed that the hypermethylation of NDN promotes cell proliferation by activating the Wnt signaling pathway through directly increasing the transcription of LRP6 in CRC. These findings might provide a new theoretical basis for the pathogenesis of CRC and facilitate the development of new therapeutic strategies against CRC.
| S-EPMC5542259 | biostudies-literature
Project description:Although expression of ribosomal protein L27 (RPL27) is upregulated in clinical colorectal cancer (CRC) tissue, to the best of our knowledge, the oncogenic role of RPL27 has not yet been defined. The present study aimed to investigate whether targeting RPL27 could alter CRC progression and determine whether RPL27 gains an extra‑ribosomal function during CRC development. Human CRC cell lines HCT116 and HT29 were transfected with RPL27‑specific small interfering RNA and proliferation was assessed in vitro and in vivo using proliferation assays, fluorescence‑activated cell sorting (FACS) and a xenograft mouse model. Furthermore, RNA sequencing, bioinformatic analysis and western blotting were conducted to explore the underlying mechanisms responsible for RPL27 silencing‑induced CRC phenotypical changes. Inhibiting RPL27 expression suppressed CRC cell proliferation and cell cycle progression and induced apoptotic cell death. Targeting RPL27 significantly inhibited growth of human CRC xenografts in nude mice. Notably, polo‑like kinase 1 (PLK1), which serves an important role in mitotic cell cycle progression and stemness, was downregulated in both HCT116 and HT29 cells following RPL27 silencing. RPL27 silencing reduced the levels of PLK1 protein and G2/M‑associated regulators such as phosphorylated cell division cycle 25C, CDK1 and cyclin B1. Silencing of RPL27 reduced the migration and invasion abilities and sphere‑forming capacity of the parental CRC cell population. In terms of phenotypical changes in cancer stem cells (CSCs), RPL27 silencing suppressed the sphere‑forming capacity of the isolated CD133+ CSC population, which was accompanied by decreased CD133 and PLK1 levels. Taken together, these findings indicated that RPL27 contributed to the promotion of CRC proliferation and stemness via PLK1 signaling and RPL27 may be a useful target in a next‑generation therapeutic strategy for both primary CRC treatment and metastasis prevention.
| S-EPMC10552708 | biostudies-literature
Project description:Gallbladder cancer (GBC) is one of the most lethal malignancies worldwide, with extremely poor prognosis. Recently, forkhead box k1 (FOXK1), a member of the FOX transcription factor family, has been reported to be correlated with tumor progression in multiple malignancies. However, the role of FOXK1 in GBC has not been elucidated. In this study, we demonstrated that the expression level of FOXK1 was elevated in human GBC tissues and associated with increased liver metastasis, poor histological differentiation, advanced TNM stage, and shorter overall survival. Knockdown of FOXK1 expression inhibited GBC cells proliferation and metastasis. Consistently, overexpression of FOXK1 promoted GBC cells progression. Mechanical investigations verified that knockdown of FOXK1 could lead to G1/S cell cycle arrest through downregulating CDK4, CDK6, cyclin D1, and cyclin E1. And FOXK1 could regulate the expression of epithelial-mesenchymal transition (EMT) related proteins E-cad, N-cad, and Vimentin. Moreover, we found that FOXK1 could regulate the activation of Akt/mTOR signaling pathway. In addition, AKT special inhibitor MK-2206 could abolish the proliferation and metastasis discrepancy between FOXK1 overexpression GBC cells and control cells, which suggested the tumorpromoting effect of FOXK1 may be partially related with the activations of Akt/mTOR signaling pathway. Collectively, our results suggested that FOXK1 promotes GBC cells progression and represent a novel prognostic biomarker and potential therapeutic target in GBC.
| S-EPMC7180204 | biostudies-literature
Project description:BACKGROUND:Long non-coding RNAs (lncRNAs) have been identified to play an important role in the development and progression of various tumors, including colorectal cancer (CRC). However, the regulatory molecular mechanism by lncRNA in CRC initiation and progression has not been fully clarified. METHODS:TCGA database was used to identify the involvement of LINC01354 in CRC. qRT-PCR and western blot were used to determine RNA and protein expression. The gain- and loss-of-function assays were conducted to explore the function of LINC01354 in the progression of CRC. In order to investigate the LINC01354-mediated mRNA in CRC tumorigenesis, we applied the profiling analysis as well as GO and KEGG analysis. Pulldown and RIP assays were applied to detect the interaction of hnRNP-D with LINC01354 and β-catenin. RESULTS:The upregulation of LINC01354 in CRC and its prognostic significance were identified by TCGA database and confirmed in CRC tissues. Functionally, forced expression of LINC01354 promoted, while knockdown of LINC01354 inhibited cell proliferation, migration and EMT phenotype formation of CRC cells. A significant enrichment of the Wnt/β-catenin signaling pathway genes under LINC01354 overexpression. In addition, LINC01354 modulated the mRNA stability of β-catenin through interacting with hnRNP-D, thereby activating Wnt/β-catenin signaling pathway. CONCLUSIONS:Our investigations proposed novel regulatory axis of LINC01354/hnRNP-D/Wnt/β-catenin, which might be in favor of exploring novel therapeutic regimens for the clinical treatment of CRC.
| S-EPMC6463672 | biostudies-other
Project description:BackgroundColorectal cancer (CRC) is one of the most malignant tumors with high incidence, yet its molecular mechanism is not fully understood, hindering the development of targeted therapy. Metabolic abnormalities are a hallmark of cancer. Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy. In this study, we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.MethodsWe performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC. Squalene epoxidase (SQLE) was identified to be highly upregulated in CRC patients. The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability, colony and organoid formation, intracellular cholesterol concentration and xenograft tumor growth. The molecular mechanism of SQLE function was explored by combining transcriptome and untargeted metabolomics analysis. Western blotting and real-time PCR were used to assess MAPK signaling activation by SQLE.ResultsSQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis. SQLE promoted CRC growth in vitro and in vivo. Inhibition of SQLE reduced the levels of calcitriol (active form of vitamin D3) and CYP24A1, followed by an increase in intracellular Ca2+ concentration. Subsequently, MAPK signaling was suppressed, resulting in the inhibition of CRC cell growth. Consistently, terbinafine, an SQLE inhibitor, suppressed CRC cell proliferation and organoid and xenograft tumor growth.ConclusionsOur findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling, highlighting SQLE as a potential therapeutic target for CRC treatment.
| S-EPMC8360641 | biostudies-literature
Project description:Colorectal cancer (CRC) is one of the most common oncological conditions worldwide, to date. MicroRNA-1290 (miR-1290) has been demonstrated to regulate its progression. We studied the role of miR-1290 in CRC progression. The gene was upregulated in CRC tissues and cells. Its overexpression promoted CRC cell proliferation analyzed by MTT assay, colony formation assay, and soft agar growth assay. In addition, miR-1290 knockdown inhibited CRC cell proliferation. We also found that miR-1290 overexpression reduced the p27 level and increased cyclin D1 at both the mRNA and protein levels, whereas miR-1290 knockdown increased p27 and reduced cyclin D1, confirming miR-1290 promoted CRC cell proliferation. Inositol polyphosphate 4-phosphatase B (INPP4B) was the target of miR-1290. Luciferase reporter assay revealed that miR-1290 directly bound to the 3'-UTR of INPP4B; the mutated seed sites in miR-1290 abrogated this effect. Double knockdown of INPP4B and miR-1290 promoted CRC cell proliferation, suggesting miR-1290 promoted CRC cell proliferation by targeting INPP4B.
| S-EPMC7844673 | biostudies-literature
Project description:Notch pathway signaling is known to promote gastric stem cell proliferation, and constitutive pathway activation induces gastric tumors via mTORC1 activation in mouse genetic models. The purpose of this study was to determine whether human gastric adenocarcinomas are similarly dependent on Notch and mTORC1 signaling for growth. Gene expression profiling of 415 human gastric adenocarcinomas in The Cancer Genome Atlas, and a small set of locally obtained gastric cancers showed enhanced expression of Notch pathway components, including Notch ligands, receptors and downstream target genes. Human gastric adenocarcinoma tissues and chemically induced mouse gastric tumors both exhibited heightened Notch and mTORC1 pathway signaling activity, as evidenced by increased expression of the NOTCH1 receptor signaling fragment NICD, the Notch target HES1, and the mTORC1 target phosphorylated S6 ribosomal protein. Pharmacologic inhibition of either Notch or mTORC1 signaling reduced growth of human gastric cancer cell lines, with combined pathway inhibition causing a further reduction in growth, suggesting that both pathways are activated to promote gastric cancer cell proliferation. Further, mTORC1 signaling was reduced after Notch inhibition suggesting that mTOR is downstream of Notch in gastric cancer cells. Analysis of human gastric organoids derived from paired control and gastric cancer tissues also exhibited reduced growth in culture after Notch or mTOR inhibition. Thus, our studies demonstrate that Notch and mTOR signaling pathways are commonly activated in human gastric cancer to promote cellular proliferation. Targeting these pathways in combination might be an effective therapeutic strategy for gastric cancer treatment.
| S-EPMC6536707 | biostudies-literature
Project description:Cortactin (CTTN) is overexpressed in various tumors, including head and neck squamous cell carcinoma and colorectal cancer (CRC), and can serve as a biomarker of cancer metastasis. We observed that CTTN promotes cancer cell proliferation in vitro and increases CRC tumor xenograft growth in vivo. CTTN expression increases EGFR protein levels and enhances the activation of the MAPK signaling pathway. CTTN expression also inhibits the ubiquitin-mediated degradation of EGFR by suppressing the coupling of c-Cbl with EGFR. CoIP experiments indicate CTTN can interact with c-Cbl in CRC cells. These results demonstrate that CTTN promotes the proliferation of CRC cells and suppresses the degradation of EGFR.
| S-EPMC5352075 | biostudies-literature