Downregulation of miR-29c promotes muscle wasting by modulating the activity of leukemia inhibitory factor in lung cancer cachexia

Kairu Xie,Hairong Xiong,Jiaxin Ye,Wen Xiao,Zhixian Chen,Changfei Yuan,Xiaoping Zhang,Hongmei Yang,Jian Shi,Wenjun Hu,Ning Xu,Zhiyong Xiong,Daojia Miao

doi:10.1186/s12935-021-02332-w

Abstract

BackgroundCancer cachexia is a wasting disorder characterized by significant weight loss, and is attributed to skeletal muscle weakness. In the process of cancer development, microRNAs act as oncogenes or tumor suppressors. Moreover, they are implicated in muscle development and wasting. This study sought to explore the mechanisms and correlation between miR-29c and muscle wasting in lung cancer cachexia.MethodsData for expression analysis were retrieved from the Cancer Genome Atlas (TCGA) database. qRT-PCR analyses were performed to explore the expression levels of miR-29c and Leukemia Inhibitory Factor (LIF). Lewis lung carcinoma (LLC) cell line was used to establish a cachexia model to explore the functions of miR-29c and LIF in lung cancer cachexia. Furthermore, in vitro (in C2C12 myotubes) and in vivo (in LLC tumor-bearing mice) experiments were performed to explore the mechanisms of miR-29c and LIF in lung cachexia.ResultsAnalysis of the lung cancer cachexia model showed that miR-29c was down-regulated, and its expression was negatively correlated with muscle catabolic activity. Overexpression of miR-29c mitigated the cachectic phenotype. Mechanistic studies showed that LIF was a direct target gene of miR-29c, and LIF was upregulated in vitro and in vivo. Analysis showed that LIF promoted muscle wasting through the JAK/STAT and MAP-kinase pathways.ConclusionsThe findings indicated that miR-29c was negatively correlated with the cachectic phenotype, and the miR-29c-LIF axis is a potential therapeutic target for cancer cachexia.

Highlights

Cancer cachexia is a wasting disorder characterized by significant weight loss, and is attributed to skeletal muscle weakness
Low expression levels of miR‐29c in lung adenocarcinoma (LUAD) tissues is correlated with survivals Previous studies reported that miR-29 family plays a role as a tumor suppressor in several cancer types
To elucidate the biological functions of miR-29c in muscle atrophy in lung cancer cachexia, LUAD data were retrieved from public databases and Kaplan Meier Plotter tools were used for survival analysis

Summary

Introduction

Cancer cachexia is a wasting disorder characterized by significant weight loss, and is attributed to skeletal muscle weakness. Cancer cachexia is a wasting syndrome characterized by irreversible weight loss and frailty that affects approximately half of cancer patients. ALP uses autophagosomes to engulf ubiquitinated proteins and organelles subsequently transfers them to autolysosomes, where the proteins are enzymatically degraded [11]. During this process, autophagy markers (LC3 and P62) are activated in the cachectic muscles of tumor-bearing mice [5]. Autophagy markers (LC3 and P62) are activated in the cachectic muscles of tumor-bearing mice [5] These findings imply that UPP and ALP are essential components of muscle catabolism activation during cancer cachexia. The mechanisms through which cancer activates muscle wasting have not been fully elucidated

Methods

Results

Discussion

Conclusion