The Pathway to Cancer Cachexia: MicroRNA-Regulated Networks in Muscle Wasting Based on Integrative Meta-Analysis.

Maeli Dal-Pai-Silva,Paula Paccielli Freire,Jakeline Santos Oliveira,Diogo de Moraes,Sarah Santiloni Cury,Geysson Javier Fernandez,Grasieli de Oliveira,Robson Francisco Carvalho,Patrícia Pintor dos Reis

doi:10.3390/ijms20081962

Maeli Dal-Pai-Silva, Paula Paccielli Freire + Show 7 more

Open Access

https://doi.org/10.3390/ijms20081962

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Abstract

Cancer cachexia is a multifactorial syndrome that leads to significant weight loss. Cachexia affects 50%–80% of cancer patients, depending on the tumor type, and is associated with 20%–40% of cancer patient deaths. Besides the efforts to identify molecular mechanisms of skeletal muscle atrophy—a key feature in cancer cachexia—no effective therapy for the syndrome is currently available. MicroRNAs are regulators of gene expression, with therapeutic potential in several muscle wasting disorders. We performed a meta-analysis of previously published gene expression data to reveal new potential microRNA–mRNA networks associated with muscle atrophy in cancer cachexia. We retrieved 52 differentially expressed genes in nine studies of muscle tissue from patients and rodent models of cancer cachexia. Next, we predicted microRNAs targeting these differentially expressed genes. We also include global microRNA expression data surveyed in atrophying skeletal muscles from previous studies as background information. We identified deregulated genes involved in the regulation of apoptosis, muscle hypertrophy, catabolism, and acute phase response. We further predicted new microRNA–mRNA interactions, such as miR-27a/Foxo1, miR-27a/Mef2c, miR-27b/Cxcl12, miR-27b/Mef2c, miR-140/Cxcl12, miR-199a/Cav1, and miR-199a/Junb, which may contribute to muscle wasting in cancer cachexia. Finally, we found drugs targeting MSTN, CXCL12, and CAMK2B, which may be considered for the development of novel therapeutic strategies for cancer cachexia. Our study has broadened the knowledge of microRNA-regulated networks that are likely associated with muscle atrophy in cancer cachexia, pointing to their involvement as potential targets for novel therapeutic strategies.

Highlights

Cachexia is a syndrome associated with pathological conditions, including sepsis, chronic obstructive pulmonary disease, heart failure, and cancer [1,2]
Our analysis identified new molecular pathways potentially involved in skeletal muscle atrophy in cancer cachexia
The meta-analysis resulted in nine studies reporting skeletal muscle gene expression data in cancer cparcehseexnitath[2e8d,2e9s,c3r6i–p4ti1o,4n3o].f pTuhbelipcrlyocaevsasiltaobsleelceacnt ctherecsatcuhdeixeisaisstusudmiems ianrcilzueddedininFitghuerem1e.taW-aenaplryessiesnint tThaebdlees1c.riTphtieosne ostfupduibeslicrleypaovrtaimlaublseclceangceenreceaxcphreexsisaiostnuddiaetsainfrcolmudepdatiinenthtseamndetam-aonuasleysmisoidneTlsabwleit1h

Summary

Introduction

Cachexia is a syndrome associated with pathological conditions, including sepsis, chronic obstructive pulmonary disease, heart failure, and cancer [1,2]. Cachexia is more prevalent in gastric or pancreatic cancer, as up to 80% of patients may develop the syndrome [5,6]. Cachexia occurs in all cancer stages, and is associated with poor prognosis, decreased treatment tolerance, and a significant reduction in quality of life [7]. Other features associated with cancer cachexia are a reduction in food intake, an increase of systemic inflammation markers like C-reactive protein, and decreased response to chemotherapy [7]. These features may increase surgical risk in cachectic patients [7,8]. There are some advances in therapeutic strategies for muscle wasting in cancer cachexia (reviewed in [4]), effective targets to treat the syndrome are still lacking

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