MiR-186-5p prevents hepatocellular carcinoma progression by targeting methyltransferase-like 3 that regulates m6A-mediated stabilization of follistatin-like 5.

Background: Hepatocellular carcinoma (HCC) is a multistep process involving sophisticated genetic, epigenetic, and transcriptional changes. However, studies on microRNA (miRNA)'s regulatory effects of N6-methyladenosine (m6A) modifications on HCC progression are limited. Methods: Cell Counting Kit-8 (CCK-8), clone formation, and Transwell assays were used to investigate changes in cancer cell proliferation, invasion, and migration. RNA m6A levels were verified using methylated RNA immunoprecipitation. Luciferase reporter assay was used to study the potential binding between miRNAs and mRNA. A mouse tumor transplant model was established to study the changes in tumor progression. Results: Follistatin-like 5 (FSTL5) was significantly downregulated in HCC and inhibited its further progression. Additionally, methyltransferase-like 3 (METTL3) reduced FSTL5 mRNA stability in an m6A-YTH domain family 2(YTHDF2)-dependent manner. Functional experiments revealed that METTL3 downregulation inhibited HCC progression by upregulating FSTL5 in vitro and in vivo. Luciferase reporter assay verified that miR-186-5p directly targets METTL3. Additionally, miR-186-5p inhibits the proliferation, migration, and invasion of HCC cells by downregulating METTL3 expression. Conclusions: The miR-186-5p/METTL3/YTHDF2/FSTL5 axis may offer new directions for targeted HCC therapy.

USP1 promotes cholangiocarcinoma progression by deubiquitinating PARP1 to prevent its proteasomal degradation.

Despite its involvement in various cancers, the function of the deubiquitinase USP1 (ubiquitin-specific protease 1) is unexplored in cholangiocarcinoma (CCA). In this study, we provide evidence that USP1 promotes CCA progression through the stabilization of Poly (ADP-ribose) polymerase 1 (PARP1), consistent with the observation that both USP1 and PARP1 are upregulated in human CCA. Proteomics and ubiquitylome analysis of USP1-overexpressing CCA cells nominated PARP1 as a top USP1 substrate. Indeed, their direct interaction was validated by a series of immunofluorescence, co-immunoprecipitation (CO-IP), and GST pull-down assays, and their interaction regions were identified using deletion mutants. Mechanistically, USP1 removes the ubiquitin chain at K197 of PARP1 to prevent its proteasomal degradation, with the consequent PARP1 stabilization being necessary and sufficient to promote the growth and metastasis of CCA in vitro and in vivo. Additionally, we identified the acetyltransferase GCN5 as acetylating USP1 at K130, enhancing the affinity between USP1 and PARP1 and further increasing PARP1 protein stabilization. Finally, both USP1 and PARP1 are significantly associated with poor survival in CCA patients. These findings describe PARP1 as a novel deubiquitination target of USP1 and a potential therapeutic target for CCA.

HSDL2 knockdown promotes the progression of cholangiocarcinoma by inhibiting ferroptosis through the P53/SLC7A11 axis.

BACKGROUND: Human hydroxysteroid dehydrogenase-like 2 (HSDL2), which regulates cancer progression, is involved in lipid metabolism. However, the role of HSDL2 in cholangiocarcinoma (CCA) and the mechanism by which it regulates CCA progression by modulating ferroptosis are unclear. METHODS: HSDL2 expression levels in CCA cells and tissues were determined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The overall survival and disease-free survival of patients with high vs. low HSDL2 expression were evaluated using Kaplan-Meier curves. The proliferation, migration, and invasion of CCA cells were assessed using Cell Counting Kit-8, colony formation, 5-ethynyl-2'-deoxyuridine DNA synthesis, and transwell assays. The effect of p53 on tumor growth was explored using a xenograft mouse model. The expression of SLC7A11 in patients with CCA was analyzed using immunofluorescence. Ferroptosis levels were measured by flow cytometry, malondialdehyde assay, and glutathione assay. HSDL2-regulated signaling pathways were analyzed by transcriptome sequencing. The correlation between p53 and SLC7A11 was assessed using bioinformatics and luciferase reporter assays. RESULTS: HSDL2 expression was lower in primary human CCA tissues than in matched adjacent non-tumorous bile duct tissues. HSDL2 downregulation was a significant risk factor for shorter overall survival and disease-free survival in patients with CCA. In addition, HSDL2 knockdown enhanced the proliferation, migration, and invasion of CCA cells. The transcriptome analysis of HSDL2 knockdown cells showed that differentially expressed genes were significantly enriched in the p53 signaling pathway, and HSDL2 downregulation increased SLC7A11 levels. These findings were consistent with the qRT-PCR and western blotting results. Other experiments showed that p53 expression modulated the effect of HSDL2 on CCA proliferation in vivo and in vitro and that p53 bound to the SLC7A11 promoter to inhibit ferroptosis. CONCLUSIONS: HSDL2 knockdown promotes CCA progression by inhibiting ferroptosis through the p53/SLC7A11 axis. Thus, HSDL2 is a potential prognostic marker and therapeutic target for CCA.

Long non-coding RNA colon cancer-associated transcript 2: role and function in human cancers.

ABSTRACT: Long non-coding RNAs (lncRNAs) are a family of non-protein-coding RNAs that span a length of over 200 nucleotides. Research reports have illustrated that lncRNAs are involved in various cellular processes and that their abnormal expression leads to the occurrence and development of various tumors. Colon cancer-associated transcript 2 (CCAT2) was first reported as an oncogene in colon cancer. LncRNA CCAT2 is abnormally expressed in hepatocellular carcinoma, cholangiocarcinoma, lung cancer, breast cancer, ovarian cancer, glioma, and other tumors. In tumor tissues, abnormally overexpressed CCAT2 can affect cell proliferation, migration, epithelial-mesenchymal transition, apoptosis, and other biological behaviors through endogenous RNAs mechanisms, various signaling pathways, transcriptional regulation, and other complex mechanisms. Additionally, the overexpression of CCAT2 is also closely related to the tumor size, tumor node metastasis (TNM) stage, survival time, and other prognostic factors, suggesting that it is a potential prognostic indicator. This article reviews the biological functions of CCAT2 and its mechanisms of action in tumors from previous studies. In this review, we attempt to provide a molecular basis for future clinical applications of lncRNA CCAT2.

A retrospective study on the clinical and pathological features of hepatic sarcomatoid carcinoma: Fourteen cases of a rare tumor.

Hepatic sarcomatoid carcinoma is a rare liver malignancy with atypical clinical symptoms and a high degree of malignancy. To improve the understanding of this disease, we collected the clinical and pathological data of 14 patients with hepatic sarcomatoid carcinoma admitted to the First Affiliated Hospital and Second Affiliated Hospital of Bengbu Medical College from 2011 to 2021 and reviewed the relevant literature. The clinical and pathological data of 14 patients with hepatic sarcomatoid carcinoma were collected from the electronic medical record system of the 2 hospitals. All clinical data were independently reviewed by 2 clinicians, and all pathological data were independently reviewed by 2 pathologists. At the same time, we reviewed the related literature on hepatic sarcomatoid carcinoma in Pubmed and CNKI. This group of 14 patients, 10 males and 4 females, aged 50-77 years. The main symptoms of the patients were abdominal pain, bloating, anorexia, fatigue or weight loss in the upper abdomen, and 3 patients were asymptomatic. On imaging, hepatic sarcomatoid carcinoma manifests as heterogeneous mass with irregular shape and unclear boundary, and computed tomography (CT)/magnetic resonance imaging (MRI) enhanced scan shows progressive or persistent heterogeneous enhancement, marginal enhancement or annular enhancement, and central necrosis. The pathological features of hepatic sarcomatoid carcinoma are the proliferation of spindle cells and pleomorphic cells, which alternate with acinar cells. Hepatic sarcomatoid carcinoma is more common in middle-aged and elderly patients, especially men, and has no characteristic clinical manifestations. Imaging examination and B-ultrasound-guided liver biopsy + immunohistochemistry can help diagnose. Radical surgery is the preferred method for hepatic sarcomatoid carcinoma, and postoperative adjuvant chemotherapy is expected to prolong patient survival.

High expression of H2A histone family member Y promotes the proliferation and autophagy of hepatocellular carcinoma cells.

Hepatocellular carcinoma is a common malignant tumor and the third most common cause of cancer-related deaths. In this study, we selected H2AFY as a potential oncogene from three online databases, and verified differential expression between normal and liver cancer tissues. Moreover, H2AFY expression was significantly correlated with the clinical characteristics and the survival of liver cancer patients. H2AFY expression was correlated with poor prognosis of liver cancer patients. H2AFY expression was also significantly higher in liver cancer cells. Knockdown and overexpression of H2AFY in liver cancer cells showed that H2AFY promoted the proliferation and clone formation of liver cancer cells but had no significant effects on the migration and invasion ability of liver cancer cells. Western blot analysis, immunohistochemistry, and immunofluorescence double staining confirmed that H2AFY upregulated LC3 and p62 expression in liver cancer tissues and cells. In conclusion, H2AFY is highly expressed in liver cancer cells and tissues, and promotes the proliferation and autophagy of liver cancer cells. H2AFY is a potential target for liver cancer therapy.Abbreviations: APLF: aprataxin pnk-like factor; HCC: Hepatocellular carcinoma; H2AFY: H2A histone family member Y.

Gastric infiltration of hepatic sarcomatoid carcinoma: A case report and literature review.

Background: Hepatic sarcomatoid carcinoma (HSC) is an extremely rare malignant tumor typically observed in clinical settings. HSC occurrence is predominantly noted in the right lobe and rarely in the left lobe of the liver. This report presents a case of sarcomatoid carcinoma that occurred in the left outer lobe of the liver, which was accompanied by gastrointestinal stromal tumors (GSTs) in the greater curvature of the stomach. In addition, the patient showed late-stage recurrence of HSC in gastric tissues. Case presentation: A 63-year-old man was concomitantly diagnosed with HSC and GST. The main clinical manifestation was fever. Abdominal computer tomography (CT) and ultrasound-guided percutaneous liver biopsy at the local hospital revealed the presence of malignant hepatic tumors. The patient approached our hospital for further treatment. The subsequent electronic gastroscopy showed multiple submucosal tumors (SMT) in the stomach. Owing to the absence of multiple metastases in other regions of the body, we performed left hepatic lobe resection with gastric partial resection. The postoperative pathological analysis confirmed the presence of HSC and GST. The patient reported feeling well 1 month after the surgery, and no obvious space-occupying lesions in other areas were noted via imaging examinations. However, 3 months later, the patient presented with pain in the upper left abdomen, and examination revealed cancer recurrence in the stomach. The surgery was repeated, and the patient recovered favorably after the procedure. Unfortunately, the patient died owing to multiple metastatic diseases 4 months after the second surgical procedure. Conclusion: HSC shows no characteristic clinical manifestations and is highly malignant. Surgical intervention is the first treatment of choice for patients with HSC. In cases of sarcomatoid cancer occurring in the left lobe of the liver, it is imperative to exercise strict vigilance against the tumor's invasion of the stomach tissue. This is particularly important when the tumor breaks through the capsule of the liver.