Long non-coding RNAs modulate tumor microenvironment to promote metastasis: novel avenue for therapeutic intervention

Abstract

Cancer is a devastating disease and the primary cause of morbidity and mortality worldwide, with cancer metastasis responsible for 90% of cancer-related deaths. Cancer metastasis is a multistep process characterized by spreading of cancer cells from the primary tumor and acquiring molecular and phenotypic changes that enable them to expand and colonize in distant organs. Despite recent advancements, the underlying molecular mechanism(s) of cancer metastasis is limited and requires further exploration. In addition to genetic alterations, epigenetic changes have been demonstrated to play an important role in the development of cancer metastasis. Long non-coding RNAs (lncRNAs) are considered one of the most critical epigenetic regulators. By regulating signaling pathways and acting as decoys, guides, and scaffolds, they modulate key molecules in every step of cancer metastasis such as dissemination of carcinoma cells, intravascular transit, and metastatic colonization. Gaining a good knowledge of the detailed molecular basis underlying lncRNAs regulating cancer metastasis may provide previously unknown therapeutic and diagnostic lncRNAs for patients with metastatic disease. In this review, we concentrate on the molecular mechanisms underlying lncRNAs in the regulation of cancer metastasis, the cross-talk with metabolic reprogramming, modulating cancer cell anoikis resistance, influencing metastatic microenvironment, and the interaction with pre-metastatic niche formation. In addition, we also discuss the clinical utility and therapeutic potential of lncRNAs for cancer treatment. Finally, we also represent areas for future research in this rapidly developing field.

Keywords: anoikis resistance; cancer; immune modulation; long non-coding RNAs; metabolic reprogramming; metastasis; tumor microenvironment.

FIGURE 1

Mechanism of long non-coding RNAs (lncRNAs) in cancer metastasis. lncRNAs play a role in cancer development and growth by regulating various processes such as metabolic reprogramming, anoikis resistance, EMT, metastatic niche, immune escape, and oncogenes or tumor suppressors.

FIGURE 2

Long non-coding RNAs (lncRNAs) by modulating metabolic reprogramming participate in tumor metastasis. lncRNAs such as PVT1, FEZF1-AS1, LINC00092, LINC00963, MACC1-AS1, HULC, GLS-AS, lnc-p23154, lnc-IGFBP4-1, TUG1, UCA1, OP15-AS1, and XLOC-006390 have been shown to modulate metabolic pathways such as glycolysis, lipid metabolism, and glutamine metabolism, leading to tumor metastasis in different organs.

FIGURE 3

Schematics showing pathways modulated by lncRNAs to induce EMT. (A) Interaction of TGF-β ligands with T-βR triggers the canonical TGF-pathway, leading to the formation of trimeric SMAD complexes (SMAD2–SMAD3–SMAD4) which act as transcription factors in the nucleus to regulate the expression of EMT-associated genes. lncRNAs, such as LINC00978 and TUG1, can modulate the TGF-β/SMAD signaling transduction by affecting the expression and phosphorylation of SMAD2/3 and SMAD4, respectively. (B) Interaction of Wnt ligands with frizzled receptors triggers the canonical Wnt pathway, leading to the release of β-catenin which binds with LEF and TCF to promote the expression of EMT-related genes. lncRNAs AFAP1-AS1 and HOTAIR modulate the Wnt/β-catenin pathway by affecting the phosphorylation of GSK3β and methylation of H3K27, respectively. (C) Interaction of Jagged/Delta-like ligands with Notch receptors triggers the canonical Notch pathway, leading to the generation of NICD which acts as a transcriptional co-activator in the nucleus. lncRNAs HNF1A-AS1 and UCA1 modulate the Notch pathway by regulating the expression of essential components and acting as ceRNA to regulate Notch signaling indirectly. (D) Growth factors activating the MEK-ERK and PI3K-AKT pathways also induce EMT through simultaneous activation of EMT-TFs. lncRNAs, such as UCA1 and HOXA-AS3, can act as ceRNA to regulate the expression of CREB1 and miR-29c, by promoting PIK3/AKT/mTOR pathway, and enhance the phosphorylation of MEK and ERK, respectively.

FIGURE 4

Long non-coding RNAs modulate tumor microenvironment. (A) lncRNA NKILA inactivates the nuclear factor-kappa beta (NF-kB) pathway in breast cancer cells. (B) Downregulation of lncRNA NKILA in tumor-infiltrating T lymphocytes leads to decreased metastatic potential. (C) In BC cells, in response to micro environmental hypoxia, activation of CamK-A triggers the activation of the NF-kB pathway, leading to increased expression of IL6, IL8, and VEGF, and enhances angiogenesis. (D) In bladder cancer metastasis, the lncRNA LNMAT1 recruits hnRNPL to the CCL2 promoter, resulting in increased expression of CCL2 through CCL2-dependent macrophage recruitment.