Transcriptome Profiles of Human Visceral Adipocytes in Obesity and Colorectal Cancer Unravel the Effects of Body Mass Index and Polyunsaturated Fatty Acids on Genes and Biological Processes Related to Tumorigenesis

Abstract

Obesity, a low-grade inflammatory condition, represents a major risk factor for the development of several pathologies including colorectal cancer (CRC). Although the adipose tissue inflammatory state is now recognized as a key player in obesity-associated morbidities, the underlying biological processes are complex and not yet precisely defined. To this end, we analyzed transcriptome profiles of human visceral adipocytes from lean and obese subjects affected or not by CRC by RNA sequencing ( n = 6 subjects/category), and validated selected modulated genes by real-time qPCR. We report that obesity and CRC, conditions characterized by the common denominator of inflammation, promote changes in the transcriptional program of adipocytes mostly involving pathways and biological processes linked to extracellular matrix remodeling, and metabolism of pyruvate, lipids and glucose. Interestingly, although the transcriptome of adipocytes shows several alterations that are common to both disorders, some modifications are unique under obesity (e.g., pathways associated with inflammation) and CRC (e.g., TGFβ signaling and extracellular matrix remodeling) and are influenced by the body mass index (e.g., processes related to cell adhesion, angiogenesis, as well as metabolism). Indeed, cancer-induced transcriptional program is deeply affected by obesity, with adipocytes from obese individuals exhibiting a more complex response to the tumor. We also report that in vitro exposure of adipocytes to ω3 and ω6 polyunsaturated fatty acids (PUFA) endowed with either anti- or pro-inflammatory properties, respectively, modulates the expression of genes involved in processes potentially relevant to carcinogenesis, as assessed by real-time qPCR. All together our results suggest that genes involved in pyruvate, glucose and lipid metabolism, fibrosis and inflammation are central in the transcriptional reprogramming of adipocytes occurring in obese and CRC-affected individuals, as well as in their response to PUFA exposure. Moreover, our results indicate that the transcriptional program of adipocytes is strongly influenced by the BMI status in CRC subjects. The dysregulation of these interrelated processes relevant for adipocyte functions may contribute to create more favorable conditions to tumor establishment or favor tumor progression, thus linking obesity and colorectal cancer.

Putative Positive Role of Inflammatory Genes in Fat Deposition Supported by Altered Gene Expression in Purified Human Adipocytes and Preadipocytes From Lean and Obese Adipose Tissues

“…Unfortunately, all of the AC and preAC samples we used in this study were puri ed from ATs distantly residing in the tumors of cancer patients (see the Materials and Methods section). It is possible that cancer could induce molecular changes in the residing AT, or vice versa [36], and the downregulated in ammatory genes in the obese condition could be a byproduct of complex interactions between cancer and the surrounding tumors. However, we think this is unlikely because the in uence of cancer over changes in gene expression in AT between the lean and obese conditions are mutually offset in the gene expression pro les and would not be detected in the DEG analysis.…”

Putative positive role of inflammatory genes in fat deposition supported by altered gene expression in purified human adipocytes and preadipocytes from lean and obese adipose tissues

“…Unfortunately, all of the AC and preAC samples we used in this study were puri ed from ATs distantly residing in the tumors of cancer patients (see the Materials and Methods section). It is possible that cancer could induce molecular changes in the residing AT, or vice versa [43], and the downregulated in ammatory genes in the obese condition could be a byproduct of complex interactions between cancer and the surrounding tumors. However, we think this is unlikely because the in uence of cancer over changes in gene expression in AT between the lean and obese conditions are mutually offset in the gene expression pro les and would not be detected in the DEG analysis.…”

Integrated Transcriptome Analysis of Human Visceral Adipocytes Unravels Dysregulated microRNA-Long Non-coding RNA-mRNA Networks in Obesity and Colorectal Cancer

“…As previously described (28), "human visceral adipose tissue (VAT) was collected from age-matched lean and obese subjects undergoing abdominal surgery or laparoscopy for benign (i.e., gallbladder disease without icterus, umbilical hernia, and uterine fibromatosis) or CRC conditions (histologically proved primary colon adenocarcinoma, stage TNM 0-III). The exclusion's criteria were: clinical evidence of active infection, recent (within 14 days) use of antibiotics/anti-inflammatory drugs, pregnancy, hormonal therapies, severe mental illness, autoimmune diseases, family history of cancer, others neoplastic diseases.…”

“…Moreover, no studies have reported the expression of miRNAs and lncRNAs in AT from CRC patients. In this regard, we recently reported that obesity and CRC, conditions characterized by the common denominator of inflammation, are associated with changes in the transcriptional program of adipocytes mostly involving pathways and biological processes linked to fibrosis, inflammation and metabolism of pyruvate, lipids, and glucose (28). In this study, we analyzed the ncRNA expression profiles, specifically miRNAs and lncRNAs, of lean and obese subjects affected or not by CRC, by RNASeq/Small RNASeq analysis.…”