LncRNA CCAT1 facilitates the progression of gastric cancer via PTBP1-mediated glycolysis enhancement

Abstract

Background Gastric cancer (GC) is one of the most prevalent malignant tumors of the digestive system. As a hallmark of cancer, energy-related metabolic reprogramming is manipulated by multiple factors, including long non-coding RNAs (lncRNAs). Notably, lncRNA CCAT1 has been identified as a crucial regulator in tumor progression. Nevertheless, the precise molecular mechanisms underlying the involvement of CCAT1 in metabolic reprogramming of GC remain unclear. Methods Gain- and loss-of-function experiments were performed to evaluate the roles of CCAT1 in tumorigenesis and glycolysis of GC. Bioinformatics analyses and mechanistic experiments, such as mass spectrometry (MS), RNA-pulldown, and RNA immunoprecipitation (RIP), were employed to reveal the potential interacting protein of CCAT1 and elucidate the regulatory mechanism of CCAT1 in GC glycolysis. Moreover, the nude mice xenograft assay was used to evaluate the effect of CCAT1 on GC cells in vivo. Results In this study, we identified that CCAT1 expression was significantly elevated in the tissues and plasma exosomes of GC patients, as well as GC cell lines. Functional experiments showed that the knockdown of CCAT1 resulted in a substantial decrease in the proliferation, migration and invasion of GC cells both in vitro and in vivo through decreasing the expression of glycolytic enzymes and glycolytic rate. Conversely, overexpression of CCAT1 exhibited contrasting effects. Mechanistically, CCAT1 interacted with PTBP1 and effectively maintained its stability by inhibiting the ubiquitin-mediated degradation process. As a critical splicing factor, PTBP1 facilitated the transition from PKM1 to PKM2, thereby augmenting the glycolytic activity of GC cells and ultimately fostering the progression of GC. Conclusions Our findings demonstrate that CCAT1 plays a significant role in promoting the proliferation, migration, and invasion of GC cells through the PTBP1/PKM2/glycolysis pathway, thus suggesting CCAT1’s potential as a biomarker and therapeutic target for GC.

Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy

“…The lncRNA colon cancer-associated transcript-1 (CCAT1), firstly identified in CRC [ 148 ], is increased expressing in GC cells and participates in promoting the malignant progression of GC through enhancing autophagy [ 149 ]. Zhang et al presented new evidence indicating that the expression of lncRNA CCAT1 was also significantly elevated in the tissues and plasma exosomes of patients with GC; moreover, lncRNA CCAT1 was confirmed to interact directly with polypyrimidine tract binding protein 1 (PTBP1) and effectively maintain its stability by inhibiting the ubiquitin-mediated degradation process, thus to facilitate the transition from PKM1 to PKM2 to augment glycolysis in GC cells [ 150 ]. It is worthy of note that the reprogrammed Warburg effect can in turn regulate many hallmarks of cancer through promoting the release of exosome by cancer cells [ 151 , 152 ].…”

The roles of long non-coding RNAs in ovarian cancer: from functions to therapeutic implications

“…(II) As transcriptional regulators, lncRNAs can bind to downstream gene promoters ( 36 ), transcription factors ( 37 , 38 ), or recruit complexes to regulate gene expression patterns ( 39 ). (III) At the post-transcriptional level, lncRNAs interact with splicing factors to splice precursor mRNAs ( 40 ), combine with RNA-binding protein and affect mRNA stability ( 41 , 42 ), and bind to proteins or mRNAs and impact their biological functions ( 43 , 44 ). (IV) LncRNA acting as microRNAs (miRNAs) sponges to regulate the expression of their targets ( 45 , 46 ).…”

The Role of Long Noncoding RNAs (lncRNAs) in Esophageal Cancer Therapy Resistance and Metastasis

“…Colon-cancer-associated transcript-1 (CCAT1), located at chromosomal region 8q24.21, is significantly upregulated in multiple types of cancer [ 57 , 58 , 59 , 60 , 61 ] and is also highly expressed in ESCC. Zhang et al demonstrated that knockdown of CCAT1 significantly suppressed cell migration in vivo and in vitro.…”