Systemic Analyses of Cuproptosis-Related lncRNAs in Pancreatic Adenocarcinoma, with a Focus on the Molecular Mechanism of LINC00853

Abstract

Pancreatic cancer (PC) is a deadly malignant digestive tumor with poor prognoses and a lack of effective treatment options. Cuproptosis, a recently identified copper-dependent programmed cell death type, has been implicated in multiple cancers. Long non-coding RNAs (lncRNAs) are also linked to the progression of PC. However, the role and prognostic values of cuproptosis-related lncRNAs in pancreatic adenocarcinoma (PAAD) remain unclear. In this study, we systemically analyzed the differential expressions and prognostic values of 672 cuproptosis-related lncRNAs in PAAD. Based on this, a prognostic signature including four lncRNAs (LINC00853, AC099850.3, AC010719.1, and AC006504.7) was constructed and was able to divide PAAD patients into high- and low-risk groups with significantly different prognoses. Next, we focused on lncRNA LINC00853. The differential expressions of LINC00853 between normal tissue and PAAD samples were validated by qRT-PCR. LINC00853 was knocked down by siRNA in PC cell lines BxPC-3 and PANC-1 and the oncogenic role of LINC00853 was validated by CCK8, colony formation, and EdU assays. Subsequently, LINC00853 knockdown cells were subjected to tumor xenograft tests and exhibited decreased tumor growth in nude mice. Mechanistically, knockdown of LINC00853 significantly reduced cellular glycolysis and enhanced cellular mitochondrial respiration levels in PC cells. Moreover, knockdown of LINC00853 decreased the protein level of a glycolytic kinase PFKFB3. Finally, glycolysis tests and functional tests using LINC00853 and HA-PFKFB3 indicated that the effects of LINC00853 on glycolysis and cell proliferation were mediated by PFKFB3. In conclusion, our systemic analyses have highlighted the important roles of cuproptosis-related lncRNAs in PAAD while the prognostic signature based on them showed excellent performance in PAAD patients and is expected to provide clinical guidance for individualized treatment. In addition, our findings provide a novel mechanism by which the LINC00853-PFKFB3 axis critically regulates aerobic glycolysis and cell proliferation in PC cells.

Analysis of disulfidptosis‐ and cuproptosis‐related LncRNAs in modulating the immune microenvironment and chemosensitivity in colon adenocarcinoma

“…Studies have shown that products of glycolysis can regulate the activity of disulfidptosis and cuproptosis pathways, thus impacting the fate of tumour cells [11,13,18]. These findings identify the significant role of glycolysis in tumour cell metabolism, underscoring the importance of investigating the interplay between disulfidptosis and cuproptosis for a better understanding of the molecular mechanisms underlying tumour cell metabolism and programmed cell death processes.…”

Epigenetic regulation of diverse cell death modalities in cancer: a focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis

“…4; Table 3). The cuproptosis-related lncRNA LINC00853 significantly enhances cellular glycolysis and cell proliferation in pancreatic cancer (PC) cells by PFKFB3 and increases the level of cellular mitochondrial respiration and tumor growth rate [102]. Meanwhile, another cuproptosisrelated lncRNA, CASC8, is highly expressed in PC, making the prognosis of PC worse.…”