NKD1 promotes the progression and 5-FU resistance of colorectal cancer via the Wnt/β-catenin signaling.

Pharmacological inhibition of the canonical Wnt/β-catenin signaling pathway sensitizes 5-fluorouracil-resistant colorectal cancer cells

The activation of the Wnt/β-catenin pathway with chemoresistance in colorectal cancer has been hypothesized. However, the use of specific inhibitors for targeting this pathway has not been well explored. In the present study, we analyze the activation of this pathway and its role in the stemness phenotype acquisition to regulate chemoresistance using our long-term 5-fluorouracil (5-FU) ‐ resistant model of colorectal cancer cells, known to present epithelial-mesenchymal transition and enhanced migration and invasion. Initially by bioinformatic analyses we demonstrate the association between 5-FU resistance genes with those of a stem cell-like phenotype in patients with colon cancer. In addition, 5-FU-resistant cells displayed stemness characteristics, with upregulation of key stem cell marker (ALDH1A1) using reverse transcription-quantitative polymerase chain reaction. Further, 5-FU-resistant cells exhibited high Wnt/β-catenin pathway activity. Interestingly, treatment with LF3, an inhibitor of this pathway, re-sensitized the 5-FU-resistant cells, decreasing their proliferation. Wnt/β-catenin pathway activation plays a role in regulating key cellular events involved in chemoresistance. The study findings suggest the use of combinatorial therapies using conventional agents, such as 5-FU, and inhibitors of this pathway, as a useful therapeutic strategy to treat patients with colorectal cancer.

Epigenetic Activation of the KDM6B‐DKK1 Axis Promotes Colorectal Cancer Peritoneal Metastasis Through Wnt/β‐Catenin‐Associated EMT

Peritoneal metastasis (PM) is a highly lethal pattern of progression in colorectal cancer (CRC), yet the specific molecular drivers and upstream regulatory mechanisms underlying this process remain incompletely understood. In the present study, public transcriptomic datasets from TCGA and GEO were integrated to identify PM‐associated genes in CRC, and prognostic relevance was evaluated using Kaplan–Meier survival analysis and Cox regression. Stable knockdown and overexpression models were established to investigate the role of DKK1 in CRC cell migration, invasion and peritoneal dissemination using Transwell assays and a mouse peritoneal metastasis model. Multi‐cohort analysis identified 86 genes specifically upregulated in PM, among which DKK1 showed the most consistent overexpression and was significantly associated with poor prognosis in patients with CRC. Functionally, DKK1 knockdown significantly suppressed CRC cell migration, invasion and peritoneal metastatic colonization in vivo, whereas DKK1 overexpression enhanced these malignant phenotypes. Mechanistically, DKK1 promoted metastasis in association with activation of the Wnt/β‐catenin signalling programme and induction of epithelial‐mesenchymal transition. Upstream analysis demonstrated that the histone demethylase KDM6B was positively correlated with DKK1 expression and directly activated DKK1 transcription by binding to its promoter and reducing H3K27me3 enrichment. Rescue experiments further indicated that the pro‐metastatic and epithelial‐mesenchymal transition‐promoting effects of KDM6B were largely dependent on DKK1. Collectively, these findings identify DKK1 as a key driver of CRC PM and establish the KDM6B‐DKK1‐Wnt/β‐catenin‐epithelial‐mesenchymal transition axis as a critical regulatory pathway in this process.

GSTT1 promotes stemness and FGFR inhibitor sensitivity in pancreatic cancer through regulation of CD133 (PROM1).

A GSTT1HighCD133High stem-like subpopulation in metastatic PDA is identified and an FGFR-dependent signaling axis that sustains this state is identified, representing a potential therapeutic vulnerability.

Pharmacological inhibition of CDK7 and CDK9 suppresses gastrointestinal (colon) cancer progression through modulation of stemness, epithelial-mesenchymal transition, and chemoresistance.

AKR1B15 promotes hepatocarcinogenesis by activating the p53-PI3K-AKT-mTOR-E2F1 signaling pathway.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, with limited biomarkers available for early diagnosis and targeted therapy. AKR1B15, a lesser-studied member of the aldo-keto reductase family, shares high sequence similarity with AKR1B10, but its role in HCC remains unclear. Therefore, this study aimed to investigate the biological function of AKR1B15 in HCC and its involvement in oncogenic signaling pathways. Bioinformatic analysis of gene expression datasets and patient tissue samples was used to evaluate AKR1B15 expression and prognostic relevance. Functional assays were conducted following AKR1B15 knockdown, including CCK-8, colony formation, transwell, wound healing, flow cytometry, and xenograft models. Western blotting and immunofluorescence were employed to assess phosphorylation of key signaling molecules. AKR1B15 expression was significantly elevated in HCC tissues and associated with higher pathologic T stage and worse disease-specific survival (P < 0.05). AKR1B15 knockdown inhibited HCC cell proliferation, invasion, and migration (P < 0.01), and promoted apoptosis (P < 0.001). In vivo, AKR1B15 depletion suppressed tumor growth and reduced Ki-67 expression. Mechanistically, silencing AKR1B15 decreased phosphorylation of p53 (Ser15), PI3K (Tyr458/199), AKT (Ser473), mTOR (Ser2448), and E2F1 (S364), indicating inhibition of the p53-PI3K-AKT-mTOR-E2F1 axis. AKR1B15 promotes HCC progression and is associated with activation of the p53-PI3K-AKT-mTOR-E2F1 signaling pathway. It may serve as a novel diagnostic marker and therapeutic target in hepatocellular carcinoma.

FGFR2 mediates the progression of colorectal cancer by promoting the expression of HIF-1α via the PI3K/AKT/mTOR pathway.

BACKGROUND Colorectal cancer (CRC) is a common malignancy worldwide, and its progression is associated with dysregulated signaling pathways. Fibroblast growth factor receptor 2 (FGFR2) is frequently overexpressed in CRC and correlated with poor prognosis, but whether it mediates hypoxia-inducible factor-1α (HIF-1α) to promote tumor progression remains unclear. METHODS The expression and prognostic value of FGFR2 and HIF-1α in CRC were analyzed via bioinformatics. Clinicopathological specimens were obtained and immunohistochemical staining was performed to explore the correlations between FGFR2 and HIF-1α expression and the clinicopathological features of CRC patients. Using CRC cell lines (HCT116 and NCI-H716), cell proliferation, transwell, wound healing, western blotting, gene activation and knockdown experiments were used to assess the effects of FGFR2 expression on cell proliferation, migration and invasion, as well as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway activity and HIF-1α expression level. A mouse xenotransplantation model was used to further clarify the regulatory effects of changes in FGFR2 expression on PI3K/AKT/mTOR pathway activity, HIF-1α expression level and CRC tumor growth in vivo. RESULTS In this study, immunohistochemical staining of tumor tissues from 72 patients with CRC confirmed that the expression level of HIF-1α in cancer tissues was higher than that in normal tissues. Bioinformatics analysis and clinicopathological analysis confirmed that the overexpression of the FGFR2 and HIF-1α genes were the independent risk factors affecting the prognosis of CRC and that the overexpression of HIF-1α was positively correlated with the increase of tumor size and FGFR2 expression. The in vitro results of this study show that FGFR2 mediates HIF-1α and affects CRC cell proliferation, migration and invasion, which is consistent with the results of bioinformatics analysis. In vitro experiments involving FGFR2 overactivation and knockdown demonstrated that FGFR2 primarily functions in regulating the PI3K/AKT/mTOR signaling pathway, which was further verified by xenotransplantation mouse model. Knockdown of FGFR2 expression curbed the growth of CRC tumors through downregulating the PI3K/AKT/mTOR signaling pathway and HIF-1α expression level. CONCLUSION FGFR2 mediates the expression of HIF-1α via activating the PI3K/AKT/mTOR signaling pathway, thereby enhancing the proliferation, migration, and invasion of CRC cells. These findings suggest that FGFR2 may serve as potential therapeutic targets for the treatment of CRC.