Long noncoding RNA OVAAL enhances nucleotide synthesis through pyruvate carboxylase to promote 5-fluorouracil resistance in gastric cancer.

5-Fluorouracil (5-FU) is widely used in gastric cancer treatment, yet 5-FU resistance remains an important clinical challenge. We established a model based on five long noncoding RNAs (lncRNA) to effectively assess the prognosis of gastric cancer patients; among them, lncRNA OVAAL was markedly upregulated in gastric cancer and associated with poor prognosis and 5-FU resistance. In vitro and in vivo assays confirmed that OVAAL promoted proliferation and 5-FU resistance of gastric cancer cells. Mechanistically, OVAAL bound with pyruvate carboxylase (PC) and stabilized PC from HSC70/CHIP-mediated ubiquitination and degradation. OVAAL knockdown reduced intracellular levels of oxaloacetate and aspartate, and the subsequent pyrimidine synthesis, which could be rescued by PC overexpression. Moreover, OVAAL knockdown increased sensitivity to 5-FU treatment, which could be reversed by PC overexpression or repletion of oxaloacetate, aspartate, or uridine. OVAAL overexpression enhanced pyrimidine synthesis to promote proliferation and 5-FU resistance of gastric cancer cells, which could be abolished by PC knockdown. Thus, OVAAL promoted gastric cancer cell proliferation and induced 5-FU resistance by enhancing pyrimidine biosynthesis to antagonize 5-FU induced thymidylate synthase dysfunction. Targeting OVAAL-mediated nucleotide metabolic reprograming would be a promising strategy to overcome chemoresistance in gastric cancer.

A novel prognostic signature based on cuproptosis-related lncRNA mining in colorectal cancer.

Background: Colorectal cancer (CRC) is a common malignant tumor that affects the large bowel or the rectum. Cuproptosis, recently discovered programmed cell death process, may play an important role in CRC tumorigenesis. Long non-coding RNAs (lncRNAs) can alter the proliferation of colorectal cancer cells through the control and activation of gene expression. To date, cuproptosis-related lncRNAs, have not been investigated as potential predictive biomarkers in colorectal cancer. Methods: The mRNA and lncRNA expression data of colorectal cancer were gathered from The Tumor Genome Atlas (TCGA) database, and Pearson correlation analysis and univariate Cox regression analysis were used to identify the lncRNAs with differential prognosis. Colorectal cancer was classified using consistent clustering, and the clinical significance of different types, tumor heterogeneity, and immune microenvironment differences was investigated. The differential lncRNAs were further screened using LASSO regression to develop a risk scoring model, which was then paired with clinicopathological variables to create a nomogram. Finally, the copy number changes in the high-risk and low-risk groups were compared. Results: Two clusters were formed based on the 28 prognostic cuproptosis-related lncRNAs, and the prognosis of cluster 2 was found to be significantly lower than that of cluster 1. Cluster 1 showed increased immune cell infiltration and immunological score, as well as strong enrichment of immune checkpoint genes. Next, LASSO regression was used to select 11 distinctive lncRNAs, and a risk score model was constructed using the training set to distinguish between high and low-risk groups. Patients in the high-risk group had a lower survival rate than those in the low-risk group, and both the test set and the total set produced consistent results. The AUC value of the ROC curve revealed the scoring model's efficacy in predicting long-term OS in patients. Moreover, the model could be used as an independent predictor when combined with a multivariate analysis of clinicopathological features, and our nomogram could be used intuitively to predict prognosis. Conclusion: Collectively, we developed a risk model using 11 differential lncRNAs and demonstrated that the model has predictive value as well as clinical and therapeutic implications for predicting prognosis in CRC patients.

LncRNA LINC01537 Promotes Gastric Cancer Metastasis and Tumorigenesis by Stabilizing RIPK4 to Activate NF-κB Signaling.

Many studies reported that long noncoding RNAs (lncRNAs) play a critical role in gastric cancer (GC) metastasis and tumorigenesis. However, the underlying mechanisms of lncRNAs in GC remain unexplored to a great extent. LINC01537 expression level was detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Its biological roles in GC were then investigated using functional experiments. In order to investigate the underlying mechanism of LINC01537 in GC, RNA pull-down, RNA immunoprecipitation, and ubiquitination assays were performed. LINC01537 was significantly overexpressed in GC tissues and associated with a poor prognosis. Functional experimental results revealed that LINC01537 promoted the proliferation, invasion, and migration of GC cells. The animal experiments revealed that LINC01537 promoted tumorigenesis and metastasis in vivo. Mechanistically, LINC01537 stabilizes RIPK4 by reducing the binding of RIPK4 to TRIM25 and reducing its ubiquitination degradation, thereby promoting the expression of the NF-κB signaling pathway. According to our findings, the LINC01537-RIPK4-NF-κB axis promoted GC metastasis and tumorigenesis.

Three-dimensional versus two-dimensional laparoscopic surgery for rectal cancer: better promote postoperative sexual and urinary function of a propensity-matched study.

Laparoscopic total mesorectal excision (TME) with autonomic nerve preservation (ANP) is a common procedure for rectal cancer (RC), associated with a high prevalence of postoperative urogenital and anorectal dysfunctions. Compared to 2D laparoscopy, 3D laparoscopy provides better depth perception of the surgical field and hand-eye coordination to achieve better outcomes. We compared the performance of 2D and 3D laparoscopy on preserving urogenital and anorectal function in TME+ANP surgery for rectal cancer using propensity-score matching. Data were collected from consecutive male patients who underwent 3D or 2D laparoscopic TME+ANP for primary RC at our institution between March 2012 and December 2020. The primary outcome was sexual and urinary function 1 year after surgery. A total of 450 male patients were eligible. After 1:1 matching, 146 cases were included in each group for analysis. One year after surgery, the prevalence of sexual dysfunction (International Index of Erectile Function score <26) was 8.22% in the 3D laparoscopic group and 44.52% in the 2D laparoscopic group, respectively (P=0.000) and a significant difference in the incidence of urinary retention was observed (n=3 and 24, respectively (P=0.000)). Moreover, blood loss, operative time, duration of hospital stay, and the time to first flatus in the 3D laparoscopic group were significantly less than in the 2D laparoscopic group. In conclusion, 3D laparoscopic TME is associated with lower incidences of postoperative sexual and urinary dysfunction than 2D laparoscopic TME for rectal cancer in male patients.

Long Non-Coding RNA STARD13-AS Suppresses Cell Proliferation And Metastasis In Colorectal Cancer.

BACKGROUND: Dysregulation of long non-coding RNAs (lncRNAs) is closely related with the progression of cancer in humans. The functional and regulatory roles of lncRNAs in colorectal cancer (CRC) are still largely unclear. The purpose of this study is to explore the function of lncRNA STARD13-AS in CRC. METHODS: The bioinformatics tool "GEPIA" was used to predict the potential expression of STARD13-AS in CRC. qRT-PCR was used to evaluate the relative expression level of STARD13-AS in CRC cells lines and tissues samples. The functional involvement of STARD13-AS in the CRC cells was assessed using MTT assay, flow cytometry, and Transwell assay. The expression levels of cyclin D, cyclin E, E-cadherin, N-cadherin, and vimentin were assessed using Western blot. RESULTS: Bioinformatics prediction and qRT-PCR results showed that STARD13-AS expression was decreased in CRC tissues. Patients with low STARD13-AS expression exhibited distant and lymphatic metastasis as well as enhancement in tumor size. STARD13-AS expression was downregulated in CRC cell lines compared to normal human colon mucosal epithelial cell line NCM460 and STARD13-AS expression in SW620 and LoVo cell lines was lowest. Moreover, we observed that while STARD13-AS overexpression suppressed the cell cycle, proliferation, migration, and invasion, while promoted apoptosis both in LoVo and SW620 cells. In addition, STARD13-AS overexpression inhibited Cyclin E, Cyclin D, N-cadherin and vimentin expression, and promoted E-cadherin expression both in LoVo and SW620 cells. CONCLUSION: Expression of STARD13-AS suppresses cell proliferation and metastasis in CRC, suggesting that STARD13-AS might act as a potential target for CRC treatment.