Cancer cachexia: molecular mechanism and pharmacological management

2021 ◽  
Vol 478 (9) ◽  
pp. 1663-1688
Author(s):  
Yonghua Li ◽  
Huan Jin ◽  
Yibing Chen ◽  
Ting Huang ◽  
Yanjun Mi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cancer Cachexia ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Life Quality ◽  
Signal Pathways ◽  
Pharmacological Management ◽  
Early Phase Trials ◽  
Molecular Substrates ◽  
Underlying Mechanisms

Cancer cachexia often occurs in malignant tumors and is a multifactorial and complex symptom characterized by wasting of skeletal muscle and adipose tissue, resulting in weight loss, poor life quality and shorter survival. The pathogenic mechanism of cancer cachexia is complex, involving a variety of molecular substrates and signal pathways. Advancements in understanding the molecular mechanisms of cancer cachexia have provided a platform for the development of new targeted therapies. Although recent outcomes of early-phase trials have showed that several drugs presented an ideal curative effect, monotherapy cannot be entirely satisfactory in the treatment of cachexia-associated symptoms due to its complex and multifactorial pathogenesis. Therefore, the lack of definitive therapeutic strategies for cancer cachexia emphasizes the need to develop a better understanding of the underlying mechanisms. Increasing evidences show that the progression of cachexia is associated with metabolic alternations, which mainly include excessive energy expenditure, increased proteolysis and mitochondrial dysfunction. In this review, we provided an overview of the key mechanisms of cancer cachexia, with a major focus on muscle atrophy, adipose tissue wasting, anorexia and fatigue and updated the latest progress of pharmacological management of cancer cachexia, thereby further advancing the interventions that can counteract cancer cachexia.

scholarly journals Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Ying Liu ◽  
Xiang Ao ◽  
Guoqiang Ji ◽  
Yuan Zhang ◽  
Wanpeng Yu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Life Quality ◽  
Therapeutic Targets ◽  
Chemotherapeutic Agents ◽  
Response To Chemotherapy ◽  
Novel Biomarkers ◽  
Related Proteins

Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.

The Role of Tumor-related LncRNA PART1 in cancer

2021 ◽  
Vol 27 ◽  
Author(s):  
Jinlan Chen ◽  
Enqing Meng ◽  
Yexiang Lin ◽  
Yujie Shen ◽  
Chengyu Hu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
Toll Like Receptor ◽  
Non Coding Rna ◽  
Regulated Expression ◽  
The One ◽  
Long Non Coding Rna

Background: As we all know, long non-coding RNA (lncRNA) affects tumor progression, which has caused a great upsurge in recent years. It can also affect the growth, migration, and invasion of tumors. When we refer to the abnormal expression of lncRNA, we will find it associated with malignant tumors. In addition, lncRNA has been proved to be a key targeted gene for the treatment of some diseases. PART1, a member of lncRNA, has been reported as a regulator in the process of tumor occurrence and development. This study aims to reveal the biological functions, specific mechanisms, and clinical significance of PART1 in various tumor cells. Methods: Through the careful search of PUBMED, the mechanisms of the effect of PART1 on tumorigenesis and development are summarized. Results: On the one hand, the up-regulated expression of PART1 plays a tumor-promoting role in tumors, including lung cancer, prostate cancer, bladder cancer and so on. On the other hand, PART1 is down-regulated in gastric cancer, glioma and other tumors to play a tumor inhibitory role. In addition, PART1 regulates tumor growth mainly by targeting microRNA such as miR-635, directly regulating the expression of proteins such as FUS/EZH2, affecting signal pathways such as the Toll-like receptor pathway, or regulating immune cells. Conclusion: PART1 is closely related to tumors by regulating a variety of molecular mechanisms. In addition, PART1 can be used as a clinical marker for the early diagnosis of tumors and plays an important role in tumor-targeted therapy.

scholarly journals Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

2011 ◽  
Vol 300 (6) ◽  
pp. E1012-E1021 ◽  
Author(s):  
Young Taek Oh ◽  
Ki-Sook Oh ◽  
Yong Min Choi ◽  
Anne Jokiaho ◽  
Casey Donovan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Nicotinic Acid ◽  
Molecular Mechanisms ◽  
Lipid Lowering ◽  
Plasma Ffa ◽  
Phosphodiesterase 3B ◽  
Altered Gene ◽  
Underlying Mechanisms

Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipid-lowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (>60%, P < 0.01), and this effect was maintained for ≥5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold ( P < 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment.

scholarly journals Dysregulated LncRNAs Act as Competitive Endogenous RNAs and Are Associated With Cervical Cancer Development in UYGHUR Women

2021 ◽  
Vol 20 ◽  
pp. 153303382198971
Author(s):  
Yanxia Chen ◽  
Dong Chen ◽  
Jing Wang ◽  
Yu Zhang ◽  
Ji Zhang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Interaction Network ◽  
Intraepithelial Neoplasia ◽  
Mature Mirnas ◽  
Western China ◽  
Cancer Development ◽  
Underlying Mechanisms ◽  
Cervical Cancer Development

Cervical cancer is one of the most malignant tumors in women, particularly those in rural and remote areas. Its underlying molecular mechanisms, including the functions of non-coding RNA (ncRNAs), require more extensive investigation. In this study, high throughput transcriptome sequencing (RNA-seq) was used to identify differentially expressed lncRNAs and mRNAs in normal, cervical intraepithelial neoplasia and cervical cancer tissues from Uyghur women in western China. Dysregulated lncRNAs were found to extensively participate in cervical cancer development, including viral carcinogenesis, cell cycle and cytokine-cytokine receptor signaling. Two miRNA-host lncRNAs, LINC00925 and MIR155HG, showed elevated expression in cervical cancer samples, but prolonged the survival time of cervical cancer patients. The 2 mature miRNAs of the above 2 lncRNAs, miR-9 and miR-155, also showed similar features in cervical cancer. In addition, we identified 545 lncRNAs with potential functions in regulating these 2 miRNAs as competing endogenous RNAs (ceRNAs). In summary, our study demonstrated the dysregulated lncRNAs/miRNAs, particularly LINC00925/miR-9 and MIR155HG/miR-155, regulate the development of cervical cancer by forming a interaction network with mRNAs, highlighting the importance of elucidating the underlying mechanisms of ncRNAs in cervical cancer development.

MBNL1 Regulates the Expression and Alternative Splicing of Genes Enriched in Cell Adhesion and Apoptosis

2021 ◽  
Author(s):  
Meijia Liu ◽  
Xianjing Song ◽  
Longbo Li ◽  
Chunli Song ◽  
Yongfeng Shi
Keyword(s):  
Cell Proliferation ◽  
Cell Adhesion ◽  
Alternative Splicing ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Signal Pathways ◽  
Apoptotic Process ◽  
Cancer Pathogenesis ◽  
Splicing Regulator ◽  
Underlying Mechanisms

Abstract Muscleblind Like Splicing Regulator 1 (MBNL1), one canonical RNA binding protein (RBP), plays important roles in the regulation of the alternative splicing (AS) on pre-mRNAs. MBNL1 has traditionally been considered involved in the pathogenesis of myotonic dystrophy. Recent researches point out that MBNL1 has an effect on cancer progress, but the underlying mechanisms are unclear. In this study, we obtained the regulated transcriptome profile of MBNL1 in HeLa cells by RNA-seq analysis. The results showed that the knockdown of MBNL1 promoted cell proliferation while inhibited apoptosis. We found 398 genes were differentially up-regulated and 277 down-regulated by MBNL1 knockdown (KD). The differentially expressed genes (DEGs) regulated by MBNL1-KD were enriched in the signal pathways of homophilic cell adhesion, apoptotic process, extracellular matrix organization and cell migration. Systematical AS analysis revealed 504 MBNL1-regulated AS events. The regulated alternative splicing genes (RASGs) were enriched in the signal pathways of apoptotic signaling pathway, positive regulation of apoptotic process, adherent junction, fatty acid elongation and DNA repair. In summary, our results demonstrate that the knockdown of MBNL1 have significant effects on cell proliferation and apoptosis by regulating the expression and alternative splicing of associated genes, illustrating the possible molecular mechanisms of MBNL1 in cancer pathogenesis and progression and other diseases.

scholarly journals Predicting Bone Metastasis Using Gene Expression-Based Machine Learning Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Somayah Albaradei ◽  
Mahmut Uludag ◽  
Maha A. Thafar ◽  
Takashi Gojobori ◽  
Magbubah Essack ◽  
...  
Keyword(s):  
Machine Learning ◽  
Adverse Effects ◽  
Predictive Value ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Life Quality ◽  
Cord Compression ◽  
Learning Models ◽  
Tcga Dataset ◽  
Machine Learning Models

Bone is the most common site of distant metastasis from malignant tumors, with the highest prevalence observed in breast and prostate cancers. Such bone metastases (BM) cause many painful skeletal-related events, such as severe bone pain, pathological fractures, spinal cord compression, and hypercalcemia, with adverse effects on life quality. Many bone-targeting agents developed based on the current understanding of BM onset’s molecular mechanisms dull these adverse effects. However, only a few studies investigated potential predictors of high risk for developing BM, despite such knowledge being critical for early interventions to prevent or delay BM. This work proposes a computational network-based pipeline that incorporates a ML/DL component to predict BM development. Based on the proposed pipeline we constructed several machine learning models. The deep neural network (DNN) model exhibited the highest prediction accuracy (AUC of 92.11%) using the top 34 featured genes ranked by betweenness centrality scores. We further used an entirely separate, “external” TCGA dataset to evaluate the robustness of this DNN model and achieved sensitivity of 85%, specificity of 80%, positive predictive value of 78.10%, negative predictive value of 80%, and AUC of 85.78%. The result shows the models’ way of learning allowed it to zoom in on the featured genes that provide the added benefit of the model displaying generic capabilities, that is, to predict BM for samples from different primary sites. Furthermore, existing experimental evidence provides confidence that about 50% of the 34 hub genes have BM-related functionality, which suggests that these common genetic markers provide vital insight about BM drivers. These findings may prompt the transformation of such a method into an artificial intelligence (AI) diagnostic tool and direct us towards mechanisms that underlie metastasis to bone events.

scholarly journals New insights into adipose tissue atrophy in cancer cachexia

2009 ◽  
Vol 68 (4) ◽  
pp. 385-392 ◽  
Author(s):  
Chen Bing ◽  
Paul Trayhurn
Keyword(s):  
Adipose Tissue ◽  
Cancer Cachexia ◽  
Molecular Mechanisms ◽  
Tissue Expansion ◽  
Experimental Models ◽  
Malignant Tumours ◽  
Morphological Examination ◽  
Fat Loss ◽  
Key Factor

Profound loss of adipose and other tissues is a hallmark of cancer cachexia, a debilitating condition associated with increased morbidity and mortality. Fat loss cannot be attributable to reduced appetite alone as it precedes the onset of anorexia and is much more severe in experimental models of cachexia than in food restriction. Morphological examination has shown marked remodelling of adipose tissue in cancer cachexia. It is characterised by the tissue containing shrunken adipocytes with a major reduction in cell size and increased fibrosis in the tissue matrix. The ultrastructure of ‘slimmed’ adipocytes has revealed severe delipidation and modifications in cell membrane conformation. Although the molecular mechanisms remain to be established, evidence suggests that altered adipocyte metabolism may lead to adipose atrophy in cancer cachexia. Increased lipolysis appears to be a key factor underlying fat loss, while inhibition of adipocyte development and lipid deposition may also contribute. Both tumour and host-derived factors are implicated in adipose atrophy. Zinc-α2-glycoprotein (ZAG), which is overexpressed by certain malignant tumours, has been identified as a novel adipokine. ZAG transcripts and protein expression in adipose tissue are up regulated in cancer cachexia but reduced with adipose tissue expansion in obesity. Studies in vitro demonstrate that recombinant ZAG stimulates lipolysis. ZAG may therefore act locally, as well as systemically, to promote lipid mobilisation in cancer cachexia. Further elucidation of ZAG function in adipose tissue may lead to novel targets for preventing adipose atrophy in malignancy.

Inter-Tissue and Intra-Tissue Co-Expression Networks in Human Metabolism: Morphological Evaluation of the Link Between Transcription Factors ERβ and NFAT in Morbid Obesity

2020 ◽  
Vol 17 (1) ◽  
pp. 63-80
Author(s):  
Athina Chasapi ◽  
Kostas Balampanis ◽  
Eleni Kourea ◽  
Fotios Kalfaretzos ◽  
Vaia Lambadiari ◽  
...  
Keyword(s):  
Morbid Obesity ◽  
Adipose Tissue ◽  
Clinicopathological Parameters ◽  
Morbidly Obese ◽  
Human Metabolism ◽  
Activated T Cells ◽  
Alcoholic Fatty Liver ◽  
Morphological Evaluation ◽  
Underlying Mechanisms

Background: Estrogen receptor β (ERβ) plays an important role in human metabolism and some of its metabolic actions are mediated by a positive “cross-talk” with Nuclear Factor of Activated T cells (NFAT) and the key metabolic transcriptional coregulator Transcriptional Intermediary Factor 2 (TIF2). Introduction: Our study is an “in situ” morphological evaluation of the communication between ERβ, NFAT and TIF2 in morbid obesity. Potential correlations with clinicopathological parameters and with the presence of diabetes and non-alcoholic fatty liver disease (NAFLD) were also explored. The aim of the present study was to determine the role of ERβ and NFAT in the underlying pathophysiology of obesity and related comorbidities. We have investigated the expression of specific proteins using immunochemistry methodologies. Methods: Our population consists of 50 morbidly obese patients undergoing planned bariatric surgery, during which biopsies were taken from visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle (SM), extramyocellular adipose tissue (EMAT) and liver and the differential protein expression was evaluated by immunohistochemistry. Results: We demonstrated an extensive intra- and inter-tissue co-expression network, which confirms the tissue-specific and integral role of each one of the investigated proteins in morbid obesity. Moreover, a beneficial role of ERβ and NFATc1 against NAFLD is implicated, whereas the distinct roles of TIF2 still remain an enigma. Conclusions: We believe that our findings will shed light on the complex underlying mechanisms and that the investigated biomarkers could represent future targets for the prevention and therapy of obesity and its comorbidities.

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