Functional prediction of long non-coding RNAs in ovarian cancer-associated fibroblasts indicate a potential role in metastasis

Abstract

Cancer-associated fibroblasts (CAFs) contribute to the poor prognosis of ovarian cancer. Unlike in tumour cells, DNA mutations are rare in CAFs, raising the likelihood of other mechanisms that regulate gene expression such as long non-coding RNAs (lncRNAs). We aimed to identify lncRNAs that contribute to the tumour-promoting phenotype of CAFs. RNA expression from 67 ovarian CAF samples and 10 normal ovarian fibroblast (NOF) samples were analysed to identify differentially expressed lncRNAs and a functional network was constructed to predict those CAF-specific lncRNAs involved in metastasis. Of the 1,970 lncRNAs available for analysis on the gene expression array used, 39 unique lncRNAs were identified as differentially expressed in CAFs versus NOFs. The predictive power of differentially expressed lncRNAs in distinguishing CAFs from NOFs were assessed using multiple multivariate models. Interrogation of known transcription factor-lncRNA interactions, transcription factor-gene interactions and construction of a context-specific interaction network identified multiple lncRNAs predicted to play a role in metastasis. We have identified novel lncRNAs in ovarian cancer that are differentially expressed in CAFs compared to NOFs and are predicted to contribute to the metastasis-promoting phenotype of CAFs.

MALAT1 promotes the colorectal cancer malignancy by increasing DCP1A expression and miR203 downregulation

“…Numerous studies have confirmed the strong correlations between lncRNAs and various human diseases, including cancers, Alzheimer's disease, and cardiovascular diseases . Some lncRNAs are reported to participate and play critical roles in tumorigenesis, including the generation, growth, and metastasis of cancers from several types of tissue origins . For instance, the expression of the lncRNA XIST is highly upregulated in bladder cancer and is involved with the development of bladder tumorigenesis, whereas SNHG5, another tumor‐related lncRNA, is overexpressed in chronic myeloid leukemia…”

“…21 Some lncRNAs are reported to participate and play critical roles in tumorigenesis, including the generation, growth, and metastasis of cancers from several types of tissue origins. [22][23][24] For instance, the expression of the lncRNA XIST is highly upregulated in bladder cancer and is involved with the development of bladder tumorigenesis, 25 whereas SNHG5, another tumor-related lncRNA, is overexpressed in chronic myeloid leukemia. 26 Our study has confirmed that the metastasis associated lung adenocarcinoma transcript 1 (MALAT1), an 8.1-kb lncRNA transcribed from the nuclear-enriched transcript 2 (NEAT2), is significantly overexpressed in colorectal cancer (CRC).…”

LncRNA HOXA11‐AS drives cisplatin resistance of human LUAD cells via modulating miR‐454‐3p/Stat3

“…Long non‐coding RNA (lncRNA) is known as a type of noncoding RNA with over 200 nucleotides in length and non‐protein coding ability . It has been certified that abnormal expression of lncRNAs plays a vital role in the progression of various cancers such as ovarian cancer, colon cancer and gastric cancer . Therefore, studying lncRNAs may be of great value in exploring the occurrence and development of tumors.…”

Role of tumor microenvironment in the pathobiology of ovarian cancer: Insights and therapeutic opportunities

“…45 These secreted ECM proteins, in turn, trigger a plethora of signaling pathways as PI3K-AKT as well as NFkB that promote OvCa spread, recurrence and chemoresistance. 45,59,60 In addition, increased number of CAFs was associated with advanced OvCa stage, higher frequency of metastases, and lymphatic and microvessel density. 48 The findings that the molecular cross-talk between cancer cells and CAFs in the OvCa TME is regulated by TGFβ/TGFβRs/SMAD pathway in CAFs and triggers multiple oncogenic pathways in OvCa cells warranted the initiation of clinical trials targeting TGFβ/TGFβRs as well as PI3K inhibitors in combination with standard of care therapy (summarized in Table 1).…”

“…Other secreted ECM proteins upregulated and secreted by CAFs include periostin, secreted phosphoprotein, and cartilage oligomeric matrix protein (COMP) . These secreted ECM proteins, in turn, trigger a plethora of signaling pathways as PI3K‐AKT as well as NFkB that promote OvCa spread, recurrence and chemoresistance . In addition, increased number of CAFs was associated with advanced OvCa stage, higher frequency of metastases, and lymphatic and microvessel density .…”