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Approximately 20% of colorectal cancer (CRC) patients are first diagnosed with metastatic colorectal cancer (mCRC) because they develop symptoms at an advanced stage. Despite advancements in treatment, patients with metastatic disease still experience inferior survival rates. Our objective is to investigate the association between long noncoding RNAs (lncRNAs) and prognosis and to explore their role in mCRC. In this study, we find that elevated expression of PCAT6 is independently linked to unfavourable survival outcomes in The Cancer Genome Atlas (TCGA) data, and this finding is further confirmed in CRC samples obtained from Fudan University Shanghai Cancer Center. Cell lines and xenograft mouse models are used to examine the impact of PCAT6 on tumor metastasis. Knockdown of PCAT6 is observed to impede the metastatic phenotype of CRC, as evidenced by functional assays, demonstrating the suppression of epithelial-mesenchymal transition (EMT) and stemness. Our findings show the significance of PCAT6 in mCRC and its potential use as a prognostic biomarker.

Currently, platinum-containing regimens are the most commonly used regimens for advanced gastric cancer patients, and chemotherapy resistance is one of the main reasons for treatment failure. Thus, it is important to reveal the mechanism of oxaliplatin resistance and to seek effective intervention strategies to improve chemotherapy sensitivity, thereby improving the survival and prognosis of gastric cancer patients. To understand the molecular mechanisms of oxaliplatin resistance, we generate an oxaliplatin-resistant gastric cancer cell line and conduct assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) for both parental and oxaliplatin-resistant AGS cells. A total of 3232 genomic regions are identified to have higher accessibility in oxaliplatin-resistant cells, and DNA-binding motif analysis identifies JUNB as the core transcription factor in the regulatory network. JUNB is overexpressed in oxaliplatin-resistant gastric cancer cells, and its upregulation is associated with poor prognosis in gastric cancer patients, which is validated by our tissue microarray data. Moreover, chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that JUNB binds to the transcriptional start site of key genes involved in the MAPK signaling pathway. Knockdown of JUNB inhibits the MAPK signaling pathway and restores sensitivity to oxaliplatin. Combined treatment with the ERK inhibitor piperlongumine or MEK inhibitor trametinib effectively overcomes oxaliplatin resistance. This study provides evidence that JUNB mediates oxaliplatin resistance in gastric cancer by activating the MAPK pathway. The combination of MAPK inhibitors with oxaliplatin overcomes resistance to oxaliplatin, providing a promising treatment opportunity for oxaliplatin-resistant gastric cancer patients.

The emergence of anti-EGFR therapy has revolutionized the treatment of colorectal cancer (CRC). However, not all patients respond consistently well. Therefore, it is imperative to conduct further research to identify the molecular mechanisms underlying the development of cetuximab resistance in CRC. In this study, we find that the expressions of many metabolism-related genes are downregulated in cetuximab-resistant CRC cells compared to their sensitive counterparts. Specifically, acetyl-CoA acyltransferase 2 (ACAA2), a key enzyme in fatty acid metabolism, is downregulated during the development of cetuximab resistance. Silencing of ACAA2 promotes proliferation and increases cetuximab tolerance in CRC cells, while overexpression of ACAA2 exerts the opposite effect. RTK-Kras signaling might contribute to the downregulation of ACAA2 expression in CRC, and ACAA2 predicts CRC prognosis in patients with Kras mutations. Collectively, our data suggest that modulating ACAA2 expression contributes to secondary cetuximab resistance in Kras wild-type CRC patients. ACAA2 expression is related to Kras mutation and demonstrates a prognostic role in CRC patients with Kras mutation. Thus, ACAA2 is a potential target in CRC with Kras mutation.

Background and purpose: Hepatocellular carcinoma (HCC) is still one of the most prevalent malignancies in China and throughout the world, while most of these patients are in intermediate or advanced stage when diagnosed. The resistance of advanced HCC to chemotherapy or interventional therapy is one of the crucial factors significantly limiting the survival and prognosis of patients. However, the molecular mechanisms involved have not been fully clarified. We previously found that the long non-coding RNA LINC00601 was highly expressed in oxaliplatin resistant HCC cells. This study aimed to explore the role and specific mechanism of LINC00601 in regulating the sensitivity of HCC cells to oxaliplatin chemotherapy, to provide a novel target to identify proper candidates for oxaliplatin chemotherapy, and the theoretical basis for the treatment of patients with advanced HCC. Methods: Human HCC cell line MHCC-97H and Hep-3B were induced to establish oxaliplatin resistant cell lines 97H-OXR and 3B-OXR by long-term low-dose oxaliplatin treatment in vitro. Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) was used to detect the expression of LINC00601 in cell lines. Cell counting kit-8 (CCK-8) assay was performed to detect the effect of LINC00601 gene silencing or overexpression on the sensitivity of HCC cells to oxaliplatin treatment. Flow cytometry and Western blot experiments were conducted to detect the alteration of cell apoptosis. Finally, Western blot and immunofluorescence staining were applied to explore the nuclear translocation of growth arrest and DNA damage-inducible protein 45α (GADD45A), and RNA pull-down together with RNA immunoprecipitation (RIP) experiments were carried out to validate the combination of LINC00601 and GADD45A. Results: Compared with the control cells, LINC00601 expression level was significantly increased in oxaliplatin resistant cells. Both induced-oxaliplatin-resistant cells and LINC00601-overexpressed MHCC-97H cells were observed to be less sensitive to oxaliplatin administration. On the contrary, the down-regulation of LINC00601 expression in oxaliplatin resistant cells significantly increased the sensitivity to oxaliplatin treatment. Meanwhile, upregulated expression of LINC00601 inhibited the apoptosis level of HCC cell lines after oxaliplatin treatment, which was consistent with the sensitivity levels of different cell lines to oxaliplatin as above. In addition, the overexpression of LINC00601 reduced the nuclear translocation of GADD45A and the expression of GADD45A in the nucleus. Furthermore, the combination of LINC00601 and GADD45A was observed. Conclusion: LINC00601 might regulate the apoptotic progress of cells after oxaliplatin chemotherapy by interfering with the nuclear translocation of GADD45A, which eventually lead to the resistance to oxaliplatin.

Background: Hepatocellular carcinoma (HCC) is inflammation-associated cancer with high incidence and poor prognosis. In the last decade, immunotherapy has become an important strategy for managing HCC., Objective: This study aimed to establish an immune-related gene signature for predicting prognosis and immunotherapy response in HCC., Methods: We identified immune-related differentially expressed genes (IRDEGs) based on The Cancer Genome Atlas (TCGA) database and the Immunology Database and Analysis Portal (ImmPort) database. The weighted gene co-expression network analysis (WGCNA) and Cox proportional hazard model were utilized to determine hub immune-related genes (IRGs). The TIDE tool and R package pRRophetic were used to assess the correlation between the immune-related gene signature and the clinical responses to immunotherapy and chemotherapy., Results: By using WGCNA combined with Cox proportional hazard model, PRC1, TOP2A, TPX2, and ANLN were identified as hub IRGs. The prognostic value of the newly developed gene signature (IRGPI) was demonstrated in both the TCGA database and the Gene Expression Omnibus (GEO) database. The TIDE tool showed that the high- and low-IRGPI groups presented significantly different tumor immune microenvironment and immunotherapy responses. Furthermore, the high-IRGPI group also had significantly lower chemoresistance to cisplatin than the low-IRGPI group., Conclusion: The IRGPI is a tool for predicting prognosis as well as responsiveness to immunotherapy and chemotherapy in HCC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)