MTV change is clinically useful in predicting both long-term survival and histological response to preoperative chemotherapy in EC patients, after determining the optimal cut-off value based on survival analysis.
Alterations in mitochondrial DNA (mtDNA) copy numbers in various human cancers have been studied, but any such changes in esophageal squamous cell carcinoma (ESCC) are not established. In the present study, we investigated the correlation of mtDNA copy number with clinicopathologic features, prognosis, and malignant potential of ESCC. MtDNA copy numbers of resected specimens from 80 patients treated with radical esophagectomy were measured by quantitative real-time PCR analyses. Human ESCC cells, TE8 and TE11, were cultured, and depletion of mtDNA content was induced by knockdown of mitochondrial transcription factor A expression or treatment with ethidium bromide. The mRNA and protein expression, proliferation, invasion, and cell cycle were investigated. The results showed that the mtDNA copy number of cancerous portions was 56.0 (37.4–234.5) percent that of non-cancerous parts and significantly lower (p<0.01). Low mtDNA copy number in resected cancerous tissues was significantly correlated with pathological depth of tumor invasion (p = 0.045) and pathological stage (p = 0.025). Patients with lower mtDNA copy number had significantly poorer 5-year overall survival compared to patients with higher levels (p<0.01). The mtDNA-depleted TE8 and TE11 cells had morphological changes and proliferated more slowly than control cells under normoxia but proliferated at almost the same rate under hypoxic conditions. In mtDNA-depleted cells, E-cadherin mRNA expression was decreased, and N-cadherin, vimentin, zeb-1, and cd44 mRNA expression was increased. Immunoblotting and flow cytometry analysis also showed downregulated E-cadherin and upregulated N-cadherin and CD44 protein in mtDNA-depleted cells. Moreover, mtDNA-depleted cells had enhanced invasion, migration, and sphere formation abilities, and the cell cycle arrest at G0/G1 phase was induced in these cells. These results suggested that mtDNA-depleted ESCC cells had mesenchymal characteristics, cancer stemness, and tolerance to hypoxia, which played important role in cancer progression. In conclusion, a low copy number of mtDNA is associated with tumor progression in ESCC.
Most colorectal cancers (CRCs) are moderately-differentiated or well-differentiated, a status that is preserved even in metastatic tumors. However, the molecular mechanisms underlying CRC differentiation remain to be elucidated. Herein, we unravel a novel posttranscriptional regulatory mechanism via a previously unappreciated LIN28B-CDX2 signaling axis that plays a critical role in mediating CRC differentiation. Owing to a large number of mRNA targets, the mRNA-binding protein LIN28B has diverse functions in development, metabolism, tissue regeneration and tumorigenesis. Our RNA-binding protein immunoprecipitation (RIP) assay revealed LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression results in enhanced CDX2 expression to promote both differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition in CRC liver metastasis mouse models. Chromatin immunoprecipitation (ChIP) sequence for CDX2 identified Alpha-Methylacyl-CoA racemase (AMACR) as a novel transcriptional target of CDX2 in the context of LIN28B overexpression. We also found AMACR enhances intestinal alkaline phosphatase (ALPi) activity, which is known as a key component of intestinal differentiation, through the upregulation of butyric acid. Overall, we demonstrate that LIN28B promotes CRC differentiation through CDX2-AMACR axis.
LG was feasible for gastric cancer patients with a HAS, but for those with a history of lower abdominal surgery or those who require total gastrectomy, surgeons should carefully consider the indications for LG.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.