Deciphering the roles of non-coding RNAs in liposarcoma development: Challenges and opportunities for translational therapeutic advances

Abstract

Liposarcoma is one of the most prevalent forms of soft tissue sarcoma, and its prognosis is highly dependent on its molecular subtypes. Non-coding RNAs (ncRNAs) like microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) can bind various cellular targets to regulate carcinogenesis. By affecting the expressions and activities of their downstream targets post-transcriptionally, dysregulations of miRNAs can alter different oncogenic signalling pathways, mediating liposarcoma progression. On the contrary, lncRNAs can sponge miRNAs to spare their downstream targets from translational repression, indirectly affecting miRNA-regulated oncogenic activities. In the past 15 years, multiple fundamental and clinical research has shown that different ncRNAs play essential roles in modulating liposarcoma development. Yet, there is a lack of an effective review report that could summarize the findings from various studies. To narrow this literature gap, this review article aimed to compare the findings from different studies on the tumour-regulatory roles of ncRNAs in liposarcoma and to understand how ncRNAs control liposarcoma progression mechanistically. Additionally, the reported findings were critically reviewed to evaluate the translational potentials of various ncRNAs in clinical applications, including employing these ncRNAs as diagnostic and prognostic biomarkers or as therapeutic targets in the management of liposarcoma. Overall, over 15 ncRNAs were reported to play essential roles in modulating different cellular pathways, including apoptosis, WNT/β-catenin, TGF-β/SMAD4, EMT, interleukin, and YAP-associated pathways to influence liposarcoma development. 28 ncRNAs were reported to be upregulated in liposarcoma tissues or circulation, whereas 11 were downregulated, making them potential candidates as liposarcoma diagnostic biomarkers. Among these ncRNAs, measuring the tissues or circulating levels of miR-155 and miR-195 was reported to help detect liposarcoma, differentiate liposarcoma subtypes, and predict the survival and treatment response of liposarcoma patients. Overall, except for a few ncRNAs like miR-155 and miR-195, current evidence to support the use of discussed ncRNAs as biomarkers and therapeutic targets in managing liposarcoma is mainly based on a single-center study with relatively small sample sizes or cell-based studies. Hence, more large-scale multi-center studies should be conducted to further confirm the sensitivity, specificity, and safety of ncRNAs as biomarkers and therapeutic targets. Instead of furthering investigation to confirm the translational values of all the discussed ncRNAs, which can be time- and cost-consuming, it would be more practical to focus on a few ncRNAs, including miR-155 and miR-195, to evaluate if they are sensitive and safe to be used as liposarcoma biomarkers and therapeutic agents or targets.

Keywords: Diagnosis; Liposarcoma; Prognosis; lncRNAs; miRNAs; ncRNAs.

Graphical abstract

Fig. 1

Interaction of various ncRNAs in modulating the progression of liposarcoma. MDM2 plays a crucial role in suppressing p53-mediated apoptosis activities, and miR-215-5p and lncRNA PILRLS can increase MDM2 activity to inhibit apoptosis, promoting liposarcoma growth [27,82]. MiR-26a-2 can repress the expression of pro-apoptotic protein, HOXA5, to increase uncontrolled cellular proliferation in liposarcoma [35]. BCL-2 and OSBP are two anti-apoptotic proteins that miR-143 and miR-195, respectively, can target, and their suppressions will lead to apoptosis induction in liposarcoma cells [90,106]. MiR-193b can target various downstream targets, including PDGFRβ, YAP1, SMAD4, and FAK, to downregulate oncogenic WNT/β-catenin and TGFβ/SMAD pathways to block liposarcoma progression [30,98]. Besides miR-193b, miR-155 can also control the WNT/β-catenin signalling activities by downregulating CK1α, enhancing the nuclear translocation of β-catenin to increase liposarcoma growth [70]. MiR-25-3p and miR-92a-3p can increase the expression of IL-6 in TAM to enhance IL-6-mediated inflammation, proliferation, and metastases in liposarcoma cells [85]. Hypoxia is a critical cellular activity that promotes cellular growth, and miR-210-3p and miR-485-5p can downregulate hypoxia activity in liposarcoma cells by inhibiting HIF-3α [119]. The activated MAPK pathway is known to drive tumourigenesis, and LINC00423 can suppress MAPK activities to reduce cellular growth in liposarcoma [28]. EMT is an essential cellular process that predisposes to cancer metastases, and miR-135b can inhibit THBS2 to increase the expression of MMP2, promoting the breakdown of the tissue basement membrane to accelerate liposarcoma invasion and metastases [75]. PAI-1 also plays a vital role in promoting cancer cell growth and migration, and miR-486 can target PAI-1 to inhibit the growth of myxoid liposarcoma [114]. LncRNA TODL can stabilize FOXM1, contributing to increased EMT and migratory activities in liposarcoma tissues [31]. The diagram was constructed using Biorender (https://app.biorender.com/gallery).

Fig. 2

(a) MiR-143 can target BCL-2 to promote apoptosis [90], whereas miR-215-5p can increase MDM2 activity to decrease p53-mediated apoptotic activity, resulting in increased liposarcoma proliferation [82]. (b) By suppressing CK1α expression, miR-155 can upregulate the WNT/β-catenin pathway to promote liposarcoma cell growth [70]. (c) MiR-193b can inhibit and repress TGFβ/SMAD and YAP pathways to regulate liposarcoma progression [30,98]. (d) Activated IL-6 pathway can promote nuclear translocation of NF-κβ and miR-25-3p and miR-92a-3p can upregulate IL-6 expression in TAM to promote IL-6 mediated oncogenic activity in liposarcoma cells [85]. (e) MiR-135 can suppress THBS2 to elevate the cellular expression of MMP2, promoting liposarcoma cell invasion and metastases [75]. The diagram was constructed using Biorender (https://app.biorender.com/gallery).

Fig. 3

Summary of upregulated and downregulated ncRNAs in liposarcoma. A total of 28 ncRNAs were shown to be upregulated in liposarcoma tissues (T), circulation (C), or both (B) forms. In contrast, 11 ncRNAs were downregulated in the liposarcoma tissues. Examples of overexpressed miRNAs in liposarcoma tissues include miR-9, miR-21, miR-26a, miR-26a-2, miR-135b, miR-155, miR-196a-5p, miR-329, miR-369-3p, miR-493, miR-495, miR-619-5p, miR-1246, miR-4454, miR-4532, and miR-6126 [29,34,75,90,[138], [139], [140], [141]]. Upregulated circulating miRNAs in liposarcoma include miR-25-3p, miR-92a-3p, miR-155, and miR-3613-3p [85,142,143]. A serum miRNA panel known as index VI was reported to be useful in confirming the diagnosis of liposarcoma, and the panel includes miR-658, miR-762, miR-4281, miR-4649-5p, miR-4665-3p, miR-4736, and miR-6836-3p [146]. Downregulated miRNAs that can be found in liposarcoma tissues include miR-133a, miR-143, miR-145, miR-144, miR-144-3p, miR-144-5p, miR-193b, miR-195, miR-451, miR-451a, miR-486-3p, and miR-486-5p [29,30,90,106,128,139,141]. For lncRNAs, TODL and PILRLS are two overexpressed lncRNAs in liposarcoma tissues [27,31], whereas LINC00423 was found to be the underexpressed lncRNAs in liposarcoma tissues [28]. The diagram was constructed using Biorender (https://app.biorender.com/gallery).

Fig. 4

Classification of the roles of ncRNAs in differentiating various types of sarcomas, predicting survival rate, and treatment response. MiRNAs that can be used to differentiate DDLPS and WDLPS include miR-15b-5p, miR-21-5p, miR-374a-5p, miR-454-3p, miR-193a-5p, miR-193b, and miR-423-5p [29,149]. On the other hand, miR-26a-5p can be used to differentiate DDLPS from different subtypes of sarcoma [150], while miR-155 is the miRNA that was shown to be upregulated in all liposarcoma subtypes except WDLPS [32]. Yu et al. reported that miR-1, miR-133, miR-145, and miR-206 can differentiate WDLPS and synovial sarcoma from other sarcomas [151]. Besides, a study reported that a total of 14 miRNAs can be used to differentiate WDLPS from different types of sarcoma, and the miRNAs include miR-17-5p, miR-20a-5p, miR-20b-5p, miR-93-5p, miR-106a-5p, miR-181a-5p, miR-193a-3p, miR-193b-3p, miR-365a-3p, miR-365b-3p, miR-21-3p, miR-29-3p, miR-221-3p, and miR-7150 [150]. Regarding the potential to predict the survival of liposarcoma patients, overexpression of miR-26a-2 [34], miR-135b [75], miR-155 [139], and miR-215-5p [82] signify low survival rate, while upregulation of miR-25-3p, miR-92a-3p, miR-195, and LINC00423 signify high survival probability [28,85,106]. On the contrary, a miRNA panel measuring the expression of miR-26b, miR-27b, miR-106b, miR-195, miR-629, miR-1260, and miR-1274b can be used to predict the response of liposarcoma patients to eribulin [154]. Among all the listed miRNAs, miR-155 can be used in differentiating types of sarcomas and predicting survival [32,139], while miR-195 can be used to predict patient survival rate and eribulin response [106,154]. The diagram was constructed using Biorender (https://app.biorender.com/gallery).