Plasma ctDNA enhances the tissue-based detection of oncodriver mutations in colorectal cancer.

PURPOSE: The advent of circulating tumor DNA (ctDNA) technology has provided a convenient and noninvasive means to continuously monitor cancer genomic data, facilitating personalized cancer treatment. This study aimed to evaluate the supplementary benefits of plasma ctDNA alongside traditional tissue-based next-generation sequencing (NGS) in identifying targetable mutations and tumor mutational burden (TMB) in colorectal cancers (CRC). METHODS: Our study involved 76 CRC patients, collecting both tissue and plasma samples for NGS. We assessed the concordance of gene mutational status between ctDNA and tissue, focusing on actionable genes such as KRAS, NRAS, PIK3CA, BRAF, and ERBB2. Logistic regression analysis was used to explore variables associated with discordance and positive mutation rates. RESULTS: In total, 26 cancer-related genes were identified. The most common variants in tumor tissues and plasma samples were in APC (57.9% vs 19.7%), TP53 (55.3% vs 22.4%) and KRAS (47.4% vs 43.4%). Tissue and ctDNA showed an overall concordance of 73.53% in detecting actionable gene mutations. Notably, plasma ctDNA improved detection for certain genes and gene pools. Variables significantly associated with discordance included gender and peritoneal metastases. TMB analysis revealed a higher detection rate in tissues compared to plasma, but combining both increased detection. CONCLUSIONS: Our study highlights the importance of analyzing both tissue and plasma for detecting actionable mutations in CRC, with plasma ctDNA offering added value. Discordance is associated with gender and peritoneal metastases, and TMB analysis can benefit from a combination of tissue and plasma data. This approach provides valuable insights for personalized CRC treatment.

ID2 promotes tumor progression and metastasis in thyroid cancer.

BACKGROUND: Inhibitor of DNA Binding 2 (ID2) plays a crucial role in tumor cell proliferation, invasion, metastasis, and stemness. Aberrant ID2 expression is associated with poor prognosis in various cancers. However, the specific function of ID2 in thyroid cancer remain unclear. METHOD: The TCGA database were utilized to explore the clinical relevance of ID2 in cancer. GO, KEGG, and TIMER were employed to predict the potential roles of ID2 in cancer. Functional analysis, including CCK-8, colony formation, transwell, wound healing, and sphere formation experiments, were conducted to determine the biological functions of ID2 in human cancers. Western blot (WB), RT-qPCR, and immunohistochemical (IHC) analyses were used to investigate the relationship between ID2 and downstream targets. RESULTS: Our study revealed significant overexpression of ID2 in various malignant tumor cells. Knocking ID2 significantly inhibited cancer cell proliferation and invasion, while overexpressing ID2 enhanced these capabilities. Additionally, ID2 mediates resistance of cancer cells to protein kinase B (or Akt) inhibitions. Further WB and IHC experiments indicated that ID2 promotes the phosphorylation activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, thereby upregulating the expression of downstream proliferation, epithelial-mesenchymal transition (EMT), and stemness-related markers. CONCLUSION: We found that ID2 significantly promotes thyroid cancer cell proliferation, migration, EMT, and stemness through the PI3K/Akt pathway. Moreover, ID2 plays a crucial role in regulating cancer immune responses. It may serve as a potential biomarker for enhancing the efficacy of chemotherapy, targeted therapy, and immunotherapy against cancer.

Correction to "Study of the Fe3O4@ZIF-8@Sor Composite Modified by Tannic Acid for the Treatment of Sorafenib-Resistant Hepatocellular Carcinoma".

[This corrects the article DOI: 10.1021/acsomega.3c04215.].

CXCL1 promotes immune escape in colorectal cancer by autophagy-mediated MHC-I degradation.

BACKGROUND: Immunotherapy is now seen as a potential remedy for colorectal cancer (CRC). Chemokines play a crucial role in tumors, including CRC, which contains CXCL1. We attempted to study how CXCL1 impacts immune escape in CRC. METHODS: Bioinformatics analysis was used to examine CXCL1 level in CRC. qRT-PCR was used to assess CXCL1 and MHC-I (HLA-A, B, C) levels. Cell Counting Kit-8 (CCK-8) was used to measure cell viability. Cytotoxicity assay kit was utilized to assay CD8+ T cell cytotoxicity against CRC. Flow cytometry tested proliferation and apoptosis of CD8+ T cells. Chemotaxis assay evaluated chemotaxis of CD8+ T cells towards CRC. Immunofluorescence examined expression of autophagy marker LC3 and localization of NBR1/MHC-I. Western blot analysis measured protein levels of chemokines CXCL9 and CXCL10, autophagy-related proteins LC3-I and LC3-II, and MHC-I (HLA-A, B, C). RESULTS: Bioinformatics analysis and qRT-PCR presented that CXCL1 was upregulated in CRC. Cell experiments demonstrated that CXCL1 overexpression promoted immune escape in CRC. Rescue experiments revealed that the autophagy inducer Rapa could attenuate the inhibitory effect of CXCL1 low expression on immune escape in CRC. Further studies showed that CXCL1 promoted immune escape in CRC by autophagy-mediated MHC-I degradation. CONCLUSION: CXCL1 promoted immune escape in CRC by autophagy-mediated MHC-I degradation, suggesting that CXCL1 may be a possible immunotherapeutic target for CRC.

Study of the Fe3O4@ZIF-8@Sor Composite Modified by Tannic Acid for the Treatment of Sorafenib-Resistant Hepatocellular Carcinoma.

Chemotherapeutic agents fail in clinical chemotherapy in the absence of targeting and acquired resistance. We, therefore, synthesized Fe3O4@ZIF-8@Sor@TA nanocomposite drugs based on the drug delivery properties of nanomaterials. ZIF-8 is a nanomaterial with a porous structure that can load anticancer drugs. The nanodrug used the paramagnetic property of Fe3O4 to deliver sorafenib (Sor) precisely to the tumor site, then used the pH responsiveness of ZIF-8 to slowly release Sor in the tumor microenvironment, and finally used tannic acid (TA) to inhibit P-glycoprotein to suppress the Sor resistance. The results of material characterization presented that the prepared material was structurally stable and was able to achieve a cumulative drug release of 38.2% at pH 5.0 for 72 h. The good biocompatibility of the composite was demonstrated by in vitro and in vivo experiments, which could improve antitumor activity and reduce Sor resistance through magnetic targeting TA. In conclusion, the Fe3O4@ZIF-8@Sor@TA material prepared in this study demonstrated high antitumor activity in hepatocellular carcinoma treatment, promising to reduce drug resistance and providing a novel research approach for cancer treatment.

Transcription factor FOXM1 promotes hepatocellular carcinoma malignant progression through activation of the WNT pathway by binding to SETDB1.

BACKGROUND: FOXM1 is a transcription factor confirmed by studies to promote the development of hepatocellular carcinoma (HCC) and various other cancers, yet the molecular mechanism remains rather enigmatic. This study attempted to unveil the function and regulatory mechanism of FOXM1 in the progression of HCC. METHODS: Bioinformatics methods first analyzed the expression of FOXM1 in HCC tissues and then screened target genes downstream of FOXM1. Possible pathways of the target gene were specified through Gene Set Enrichment Analysis (GSEA). After using qRT-PCR to measure the expression of FOXM1 and its downstream regulatory gene SETDB1 in HCC tissues, ChIP and dual-luciferase assays were employed and verified the binding relationship between FOXM1 and the promoter of SETDB1. Then the effects of the FOXM1/SETDB1/Wnt pathway on the proliferation, migration, and invasion of HCC cells were profiled by CCK-8, colony formation, wound healing, and transwell assays. WNT and EMT-related protein expression levels were detected by western blot and immunofluorescence assay, respectively. RESULTS: The bioinformatics prediction showed that SETDB1 was the target downstream of FOXM1, and their binding relationship was verified by ChIP and dual-luciferase assays. Cell experiments showed that FOXM1 could enhance the proliferative, migratory, and invasive abilities of HCC cells through binding to SETDB1. Rescue assay suggested that the activation of key genes of the WNT pathway and EMT-related genes were part of the regulatory mechanism that FOXM1 bound to SETDB1. CONCLUSION: This study found that FOXM1 could bind with SETDB1 and hence activate the WNT signaling pathway to promote the malignant progression of HCC. It indicated that FOXM1 could be the possible target for treating HCC.

Transcription Factor E2F8 Promotes Cisplatin Resistance in Hepatocellular Carcinoma by Regulating DNA Damage via NUSAP1.

DNA damage repair has been the key mechanism of cisplatin resistance in hepatocellular carcinoma (HCC). The present study elucidated the molecular mechanism by which nucleolar and spindle-associated protein 1 (NUSAP1) influenced cisplatin tolerance in HCC by regulating DNA damage. First, high mRNA expression of E2F8 and NUSAP1 in HCC was detected by real-time quantitative PCR in cells and tumor tissue. The interaction between E2F8 and NUSAP1 was confirmed by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays that E2F8 bound to the promoter region of NUSAP1 and regulated its transcriptional activity. The effects of the E2F8/NUSAP1 axis on cell viability, cell cycle, DNA damage protein γ-H2AX, and cisplatin resistance were investigated by CCK-8, flow cytometry, comet detection, and western blot. The results showed that NUSAP1 knockdown blocked the cell cycle in G0/G1 phase, promoted cisplatin-induced DNA damage, and enhanced cisplatin sensitivity in HCC. Overexpressed E2F8 promoted cell cycle arrest by silencing NUSAP1 in HCC, and promoting DNA damage as well as cisplatin sensitivity. In conclusion, our results suggested that E2F8 enhanced the chemoresistance of HCC cells to cisplatin by activating NUSAP1 to inhibit DNA damage, which provides a basis for describing new therapeutic targets that effectively exacerbate DNA damage and improve the chemical sensitivity of HCC to cisplatin.

Uplift resistance capacity of anchor piles used in marine aquaculture.

Anchor piles are widely used in marine aquaculture, and the safety is largely determined by the uplift resistance capacity,especially in harsh ocean environments. However, there are few practical guides to the design and installation of the anchor piles for mooring the body of marine aquaculture equipment. Laboratory experiments were conducted to investigate the effect of the initial tension angle, pile diameter, embedded depth, and pile configuration on the uplift resistance capacity of anchor piles under oblique loads. CCD camera and load cell were utilized to measure the corresponding displacement and load, respectively. The results show that increasing the initial tension angle of circular and square single piles can significantly improve the uplift resistance capacity. The failure load of the square single pile was slightly higher than that of the circular single pile. Increasing the pile diameter can effectively improve the failure load and delay the development speed of the pile top displacement. Increasing the embedded depth can effectively improve the failure load and increase the lateral displacement of the pile top. The uplift resistance capacity of the dual anchor piles was better than that of the single anchor piles. The layout configuration has little effect on the failure load, but has a large effect on the displacement development.