Hongying Liao

Cisplatin (DDP)-based chemotherapy serves as a foundational cornerstone in the clinical management of esophageal squamous cell carcinoma (ESCC). However, intrinsic or acquired resistance to DDP persists as a significant clinical challenge, severely undermining therapeutic efficacy and contributing to unfavorable patient prognoses. Through functional screening with a CRISPR/Cas9 knockout library, transcriptomic profiling of cisplatin-resistant cell lines and clinical specimens, and in vitro/in vivo validation assays, we identified PHKG2 as a key mediator of cisplatin resistance in ESCC. Mechanistically, PHKG2-mediated cisplatin resistance is driven by the phosphorylation of IGF2BP3 at residues T225 and T306. This post-translational modification enhances IGF2BP3 phase separation, thereby stabilizing CXCL8 mRNA in an m6A-dependent manner. Furthermore, increased CXCL8 secretion by ESCC cells induces the polarization of M0 macrophages toward an M2 phenotype within the tumor immune microenvironment, which subsequently suppresses the cytotoxicity of CD8⁺ T cells and fosters an immunosuppressive microenvironment in ESCC. Significantly, pharmacological inhibition of PHKG2 using prexasertib notably curtails ESCC cell proliferation and enhances cisplatin sensitivity. This study underscores the promising potential of targeting PHKG2 as a therapeutic approach to overcome cisplatin resistance in ESCC.

Background: Esophageal squamous cell carcinoma (ESCC) is a prevalent gastrointestinal malignancy in China and is associated with a poor prognosis and limited therapeutic options. EZR encodes Ezrin, a key scaffold protein that bridges the cell membrane and cytoskeleton. Its aberrant upregulation and carcinogenic role in driving malignant progression across numerous human malignancies has been established. However, the expression profile, specific biological functions, and underlying molecular mechanisms of EZR in ESCC remain largely unclear, which has limited the exploration and development of novel targeted therapeutic strategies against ESCC. This study aims to explore the role of EZR in the malignant progression of ESCC, identify its potential downstream molecules, and screen for its potential interacting proteins, so as to reveal the key mechanism by which EZR regulates ESCC progression. Methods: Bioinformatics analysis was performed using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Meanwhile, EZR protein expression in clinical ESCC tissues and paired adjacent normal tissues was determined by immunohistochemistry (IHC) and further validated in ESCC cell lines via Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). Stable EZR-knockdown ESCC cell lines were constructed, and in vitro functions (proliferation, colony formation, migration, and invasion) were evaluated via Cell Counting Kit-8 (CCK-8), colony formation, wound healing, and Transwell assays. In vivo tumor growth and metastasis were assessed with nude mouse xenograft and zebrafish tumor migration models. Enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA), were conducted to examine regulatory pathways. Focal adhesion activity and EGFR/PI3K-AKT pathway activation were detected via Western blotting. Exogenous coimmunoprecipitation (Co-IP) with flag antibody in HEK293T cells was performed to verify the Ezrin-EGFR protein interaction. Results: EZR was significantly upregulated in ESCC tissues and cell lines, and its high expression was associated with poor immune infiltration and unfavorable prognosis. EZR knockdown markedly suppressed ESCC cell proliferation, colony formation, migration, and invasion in vitro, and it inhibited xenograft growth and tumor cell distant metastasis in vivo. Regarding mechanism, EZR silencing did not alter classic epithelial-mesenchymal transition (EMT) markers but did impair focal adhesion activity to inhibit cell migration. Furthermore, EZR knockdown blocked EGF-induced EGFR phosphorylation and inactivated the downstream PI3K/AKT pathway. Exogenous Co-IP confirmed a protein-protein interaction between flag-tagged Ezrin and EGFR. Conclusions: EZR is an oncogene that mediates the malignant progression of ESCC through two pathways: it impairs cell migration and invasion by attenuating focal adhesion activity, and inhibits cell proliferation by reducing EGFR activation-mediated PI3K-AKT signaling axis activation. These findings clarify the mechanism by which EZR contributes to ESCC progression and suggest a promising therapeutic target for ESCC treatment.

One of the main characteristics of tumor metabolite reprogramming is enhanced glycolysis, and Pyruvate Kinase M2(PKM2) is a crucial enzyme that limits the pace of glycometabolism. Although PKM2 has been proven to affect the development of some cancers, a pan-cancer analysis of PKM2 has not yet been performed. We analyzed the expression and prognosis of PKM2 in pan-cancer using multiple databases. We performed epigenetic, functional enrichment, immune cell infiltration, immune checkpoint, and drug sensitivity analyses of PKM2. PKM2 was found to be significantly upregulated in most malignancies and associated with a bad prognosis. In some cancers, the PKM2 DNA promoter was hypomethylated. The expression of PKM2 was positively linked with most m6A-methylation-related genes in pan-cancer. The functions of PKM2 were primarily associated with the regulation of the immune system, glycolysis, hypoxia, angiogenesis, and epithelial-mesenchymal transition. PKM2 was favorably associated with neutrophils and cancer-associated fibroblasts in the tumor microenvironment of most cancers. Importantly, PKM2 showed a strikingly high correlation with CD274 (PD-L1), CD276, TGF-β1, VEGFA, and HAVCR2 in most cancers. Finally, using experiments, it was confirmed that silencing PKM2 could increase the sensitivity of esophageal squamous cell carcinoma to cisplatin by regulating autophagy. PKM2 affects autophagy - regulated tumor cell tolerance to chemotherapy, providing future research directions for solving tumor chemotherapy resistance.

The study aims to evaluate the survival impact of primary tumor resection (PTR) on thoracic esophageal cancer with distant metastasis(TECDM). Data of patients with TECDM was collected from the Surveillance, Epidemiology, and End Results database(SEER) from 2010 to 2020. A 1:1 propensity-score matching(PSM) analysis was employed to minimize heterogeneity between the groups. Total 7733 patients with TECDM were included in the analysis, of which 121 underwent primary tumor resection and 7612 did not. Patients who underwent primary tumor resection exhibited better median overall survival(OS) and median cancer-specific survival(CSS) compared to those who did not, in both the overall and PSM cohort. In the PSM cohort, the median OS was 11 months (95% CI, 9 to 13 months) for TECDM patients who underwent PTR, compared to 7 months (95% CI, 5 to 9 months) for those who did not. Furthermore, Cox proportional hazards models indicated that PTR was a significantly protective factor for TECDM patients in OS (HR: 0.5529; 95% CI, 0.5196 to 0.7730, P < 0.001) and CSS (HR:0.5869 ; 95% CI, 0.479 to 0.7192, P < 0.001). In conclusion, primary tumor resection is associated with improved overall survival and cancer-specific survival in thoracic esophageal cancer patients with distant metastasis.

Background: The survival benefits of pulmonary metastasectomy (PM) in colorectal cancer (CRC) patients with pulmonary metastasis remain controversial. This study aimed to assess the survival effect of PM on CRC patients with pulmonary metastasis. Methods: Data from CRC patients with pulmonary metastasis were collected from the Surveillance, Epidemiology, and End Results database between 2010 and 2020. A 1:1 propensity score matching (PSM) analysis was employed to minimize heterogeneity between the groups. Kaplan–Meier analysis was performed to evaluate the overall survival (OS) of CRC patients with pulmonary metastasis who underwent PM. Results: A total of 1,399 CRC patients with pulmonary metastasis were included; 140 patients and 1,259 patients underwent PM and did not, respectively. After PSM, there were 140 patients in each group. Patients who underwent PM demonstrated a longer median OS than those who did not, in both the overall cohort and the PSM cohort. In the PSM cohort, the median OS was 51 months (95% confidence interval [CI], 45–64 months) for CRC patients with pulmonary metastasis who underwent PM and 36 months (95% CI, 31–42 months) for those who did not undergo PM. Additionally, Cox proportional hazard models indicated that PM was a significant protective factor for OS in CRC patients with pulmonary metastasis (hazard ratio: 0.57; 95% CI, 0.41–0.80, P < 0.01). Conclusion: PM prolongs the survival of CRC patients with pulmonary metastasis.

Background: Lung cancer remains a global health challenge, with an incidence of 23% and an overall 5-year survival of only 19%, as nearly half newly diagnosed cases are at the advanced stages. Among Asian patients, over 50% of lung cancer cases carry epidermal growth factor receptor (EGFR) mutations, highlighting the significance of targeted therapy, mainly EGFR tyrosine kinase inhibitors (TKIs). However, acquired resistance to EGFR-TKIs inevitably occurs, representing a persisting challenge in cancer therapy. Malignant pleural effusion, characterized by lack of blood circulation in the pleural cavity, is commonly found in patients who develop resistance to EGFR-TKIs. Therefore, with traditional drug administration methods, primarily oral or intravenous, drug concentration within the pleural cavity is often insufficient. Hence, traditional therapy, which consists of oral and intravenous medication, along with pleural cavity drainage, often fails to yield a satisfactory outcome. Case Description: We report a case in which hyperthermic intrathoracic chemotherapy (HITHOC) was administered in a 50-year-old male patient with malignant pleural effusion and resistance to third-generation TKIs. HITHOC significantly reduced the tumor burden of the patient and helped restore sensitivity to third-generation TKIs. Conclusions: We believe that HITHOC can efficiently improve the drug concentration within the pleural cavity, thereby reducing the tumor burden and eliminating potential TKI-resistant tumor subclones in the patient. This mode of therapy may prove valuable in overcoming TKI resistance.

Background FOXF2 was reported to involve in a variety of biological behaviors that include the development of the central nervous system, tissue homeostasis, epithelia-mesenchymal interactions, regulation of embryonic development, and organogenesis. Purpose Understanding how FOXF2 influences the growth and development of cancer could provide valuable insights for researchers to develop novel therapeutic strategies. Results In this review, we investigate the underlying impact of FOXF2 on tumor cells, including the transformation of cellular phenotype, capacity for migration, invasion, and proliferation, colonization of circulating cells, and formation of metastatic nodules. In addition, we discuss the molecular mechanisms of FOXF2 in different cancers, including hepatocellular, esophageal, breast, colon, lung, prostate gland, as well as its role in embryonic development. Conclusion FOXF2 is a gene encoding a forkhead transcription factor belonging to the Forkhead Box family. The protein functions by recruiting activation transcription factors and basic components to activate the transcription of genes that interact with the complex. This review provides an in-depth analysis of the FOXF2’s function and pleiotropic roles in cancer development and progression.

Background: FOXF2, a member of the transcription factor FOX family proteins, plays a key role in tumorigenesis and tumor aggressiveness. However, the potential molecular mechanism of FOXF2 in esophageal squamous cell carcinoma (ESCC) remains largely unknown. Exploring its role and mechanism in ESCC progression may help identify new diagnostic markers and therapeutic targets. The aim of this study is to investigate the potential functions of the FOXF2 gene within the context of ESCC and to elucidate the underlying molecular pathways involved. Methods: Using the GoMiner database, GeneCard database, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and the COMPARTMENTS subcellular localization database, we identified the most likely downstream molecule of the FOXF2 gene, EZR; the subcellular locations of FOXF2 and EZR; the possible biological pathways [Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)]; and the protein interactions networks of the EZR gene enriched from the OMICS datasets via Metascape. We also used The Cancer Genome Atlas database to analyze the correlation between EZR and ERBB signaling pathway. In addition, we verified the RNA and protein expression of the target genes using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, we employed Western blot analysis and plasmid transfection and lentiviral infection techniques to gene edit FOXF2 and EZR in different EC cells to obtain stable overexpression or knockdown of the cell lines. This was followed by ex vivo and in vivo experiments including migration assay, cell scratch assay, clone formation assay, and a xenotransplantation mouse model to validate the functional phenotype of the gene-edited cells. Results: We found that knockdown of FOXF2 expression significantly enhanced the growth, invasion, and metastasis of ESCC cells both in vitro and in vivo. Moreover, we demonstrated that FOXF2 was predominantly expressed in the nucleus and directly interacted with EZR, thereby inhibiting EZR transcriptional expression, resulting in suppressed ERBB2 signal function, ultimately halting ESCC growth and metastasis. Conclusions: Taken together, these results reveal the tumor-suppressive functions of FOXF2 in inhibiting EZR-mediated ERBB2 activation, suggesting that FOXF2 could serve as a potential novel predicting prognostic biomarker for ESCC.

Background: The treatment of lung adenocarcinoma is difficult due to the limited therapeutic options. Cancer-associated fibroblasts play an important role in the development of cancers. This study aimed to identify a promising molecular target associated with cancer-associated fibroblasts for the treatment of lung adenocarcinoma. Methods: The Cancer Genome Atlas lung adenocarcinoma dataset was used to screen hub genes associated with cancer-associated fibroblasts via the EPIC algorithm and Weighted Gene Co-expression Network Analysis. Multiple databases were used together with our data to verify the differential expression and survival of COL11A1. Functional enrichment analysis and the single-cell TISCH database were used to elucidate the mechanisms underlying COL11A1 expression. The correlation between COL11A1 and immune checkpoint genes in human cancers was also evaluated. Results: Using the EPIC algorithm and Weighted Gene Co-expression Network Analysis, 13 hub genes associated with cancer-associated fibroblasts in lung adenocarcinoma were screened. Using the GEPIA database, Kaplan-Meier Plotter database, GSE72094, GSE75037, GSE32863, and our immunohistochemistry experiment data, we confirmed that COL11A1 overexpresses in lung adenocarcinoma and that high expression of COL11A1 is associated with a poor prognosis. COL11A1 has a genetic alteration frequency of 22% in patients with lung adenocarcinoma. COL11A1 is involved in the extracellular matrix activities of lung adenocarcinoma. Using the TISCH database, we found that COL11A1 is mainly expressed by cancer-associated fibroblasts in the tumor microenvironment rather than by lung adenocarcinoma cells. Finally, we found that COL11A1 is positively correlated with HAVCR2(TIM3), CD274 (PD-L1), CTLA4, and LAG3 in lung adenocarcinoma. Conclusion: COL11A1 may be expressed and secreted by cancer-associated fibroblasts, and a high expression of COL11A1 may result in T cell exhaustion in the tumor microenvironment of lung adenocarcinoma. COL11A1 may serve as an attractive biomarker to provide new insights into cancer therapeutics.