The long noncoding RNA MALAT1 modulates adipose loss in cancer-associated cachexia by suppressing adipogenesis through PPAR-γ

Abstract

Background Cancer-associated cachexia is a multifactorial syndrome defined by progressive weight loss with ongoing loss of adipose tissue and skeletal muscle. Adipose loss occurs in the early stage of cachexia and is associated with reduced quality of life and survival time. Although numerous lncRNAs are regarded as novel regulators in adipose metabolism, the role of lncRNAs that selectively modulate the development of adipose loss in cachexia remains limited. Methods In this study, we analyzed microarray data of lncRNAs in adipose loss and further explored the function and mechanism of MALAT1 in adipose loss. First, we explored the expression and function of MALAT1 in adipose cell by quantitative PCR and RNA knockdown. Subsequently, the mechanism of MALAT1 involvement in adipose loss was analyzed via RNA-seq, bioinformatics analysis and reporter gene assay. Finally, we explored the clinical significance of MALAT1 through correlation analysis. Results Cellular experiments revealed that knocking down MALAT1 significantly inhibited the process of adipogenesis. RNA-seq data showed that numerous adipogenic genes were downregulated upon MALAT1 knockdown. A protein–protein interaction network analysis identified PPAR-γ as the central node transcription factor, the inhibition of which explains the downregulation of numerous adipogenic genes. A reporter gene assay suggested that MALAT1 can regulate the gene expression of PPAR-γ at the transcriptional level. Moreover, MALAT1 was weakly expressed in the subcutaneous white adipose tissue of cancer-associated cachexia patients and was related to low fat mass index and poor prognosis in cancer patients. Conclusions This study indicated that MALAT1 is associated with adipose loss in cancer-associated cachexia by regulating adipogenesis through PPAR-γ, which may potentially be a novel target for the diagnosis and treatment of cancer-associated cachexia in the clinic.

Effects of laparoscopic sleeve gastrectomy on serum lncRNA levels in obese patients

“…However, the underlying biological mechanisms are less understood as obesity is a complex disease including biochemical and genetic factors. The current knowledge of the significant roles of obesity-related biomarkers in disease development is inadequate [18,19]. An increasing number of epidemiological studies have investigated the relationship between biomarkers associated with obesity and disease risk.…”

Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer

“…The long non-coding RNA MALAT1 acts upstream of PPARγ and might directly activate the PPARγ promoter to induce adipogenesis. Low expression of MALAT1 in cancer patients is associated with tumor cachexia and poor survival [ 424 ]. The esophageal adenocarcinoma-specific master regulator transcription factors (MRTFs) ELF3, KLF5, GATA6, and EHF activate PPARγ.…”

LncRNA-Mediated Adipogenesis in Different Adipocytes

“…[121]. Han et al [122] found that MALAT1 is mainly located in the nucleus, is expressed in fat cells, and is underexpressed in the subcutaneous white adipose tissue of cancer-related cachexia patients, which is related to the low-fat mass index and poor prognosis of cancer. Subsequent experiments showed that the expression of MALAT1 positively correlated with that of FABP4 and LPL genes that regulate, indicating that MALAT1 promotes fat formation [123].…”