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Clinical Significance of Angiogenesis Regulating lncRNAs in Cancer: History
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Contributor: Peace Mabeta

In many cancers the current staging has limitations in terms of determining prognosis. Biomarkers are critical in completing clinical staging and improving the prediction of lymph node metastasis as well as in determining cancer prognosis. Several lncRNAs are over-expressed in various cancer cell lines, as well as in preclinical cancer models and patients. These lncRNAs have been explored for possible clinical application as biomarkers and as targets for therapeutic intervention.

  • vascular endothelial growth factor
  • lncRNA
  • tumor angiogenesis

1. Angiogenesis Regulating Long Noncoding RNAs: Role as Cancer Biomarkers

Investigations have revealed significant correlations between patient outcome and the expression levels of some of the angiogenesis regulating long noncoding ribonucleic acids (lncRNAs) such as UBE2CP3, LINC00312, and HOTAIR [1][2][3]. In breast cancer, UBE2CP3 is highly expressed, promotes tumor angiogenesis, and is also associated with poor prognosis [4][3]. In patients with HCC, UBE2CP3 expression levels correlated with vessel density. Furthermore, patients overexpressing UBE2CP3 were found to exhibit a median overall survival (OS) that was lower than that of HCC patients with tumours that did not express UBE2CP3 [5]. Interestingly, the expression of UBE2CP3 is restricted to the tumour and has not been detected in the para-tumour tissue [5]. On the other hand, meta-analysis revealed that TUG1, SPRY4-1T1, and HULC did not correlate with lymph node metastasis in various cancers [5][6]. However, a correlation could be established between the expression levels of these three lncRNAs and low overall survival in cancer patients [7].
LncRNA associated with microvascular invasion in hepatocellular carcinoma (MVIH)​ was initially identified in hepatocellular carcinoma but was later also detected in other neoplasms such as breast cancer [2][8]. Its overexpression in HCC patients correlates with increased tumour vascularization and metastasis [6][8]. In a mouse model of HCC, the induced overexpression of MVIH stimulated angiogenesis and promoted tumour growth and metastasis [9]. Of note is that, in breast and non-small cell lung cancers, MVIH is associated with poor prognosis, while in HCC patients who undergo hepatectomy it is a predictor of low recurrence free survival [10][9][11][12]. UBE2CP3 and MVIH could thus be useful markers for monitoring patient response to cancer therapy [6][13][14]. HOX transcript anti-sense RNA (HOTAIR), the first antisense transcription lncRNA to be discovered, is overexpressed in cancer tissues compared to normal tissues. It is linked to the development of gastric cancer (GC), breast cancer, lung cancer, and liver cancer [6]. HOTAIR promotes the expression of Vascular endothelial growth factor (VEGF)​ and activates the PI3K/AKT/multidrug resistance protein 1 (MRP1) pathway through direct binding to miR-126. Data has shown that serum HOTAIR levels were higher in patients with oesophageal squamous carcinoma when compared to controls without cancer, and that HOTAIR levels correlate with tumour node metastasis (TNM) stage [15]. In gastric cancer, HOTAIR correlates with lymph node and distant metastasis, while in colorectal carcinomas it is associated with advanced stage and metastases [16]. H19, another angiogenesis-regulating lncRNA, is also associated with lymph node metastasis [6]. HOTAIR and H19 could serve as prognostic biomarkers in both gastric and colorectal carcinomas. Moreover, HOTAIR is currently used as a prognostic marker for recurrence in patients who have undergone liver transplantation [17]. Additionally, several studies have shown that blood levels of HOTAIR are good predictors of disease outcome [18]. HOTAIR and PVT1 detected in the saliva were identified as possible biomarkers early pancreatic disease [19][20]. Another lncRNA, Homebox A11 antisense (HOXA11as) was highly expressed in cancerous tissue, and its expression showed a significant correlation with clinicopathological features in serous ovarian cancer (SOC) [21]. Additionally, patients with an elevated expression of HOXA11as had a significantly shorter progression-free and overall survival rates. These observations provide a basis for the further studies and the development of these lncRNAs as biomarkers.

2. Therapeutic Targeting of lncRNAs in Cancer Angiogenesis

Several lncRNAs that regulate tumor angiogenesis were shown to be aberrantly expressed in many cancers, making them an attractive target for drug design. Moreover, many of these lncRNAs are not readily detectable in normal tissue, and some are both tissue and cancer subtype specific [6][22]. A few studies have investigated the potential use of these lncRNAs as targets for cancer therapy mainly in preclinical models [23][24][25]. The silencing of SPRYT4-IT1, inhibits the migration of oesophageal squamous cell carcinoma cell in vitro, while NEAT1 suppression inhibits tumor cell growth through p53 [25]. In several independent studies, MALAT1 promoted angiogenesis in vitro and its silencing led to an increase in EC migration, while the inhibition of MALAT1 expression by GapmeR inhibited EC sprout formation [26][23][24]. HOTAIR expression levels were found to be high in cisplatin resistant ovarian cancer cells. The knockdown of HOTAIR in these cells led to the inhibition of tumor cell growth and invasiveness [27]. The silencing of HOTAIR by siRNAs inhibits tumour cell invasiveness in breast cancer and reduces tumor growth in pancreatic cancer [25]. Furthermore, the knockdown of HOTAIR has been shown to improve the sensitivity of tumour cells to cisplatin and doxorubicin. The silencing of CRNDE in colorectal cancer cells suppresses tumor cell growth and reduces resistance to chemotherapy [28]. While these studies have yielded positive results, they are in their infancy and much remains to be done. Additionally, recent reports on the mechanism of some lncRNAs reveal anecdotal results. The LINC000961 gene was shown to yield two molecules with different and opposing effects on angiogenesis [29]. Similarly, another angiogenesis-regulating lncRNA that has been explored for drug targeting is LincRNA-p21 [30]. While some studies showed that it correlates with microvessel density and that its silencing reduces VEGF expression, it was also found to be downregulated in tumour tissue [30]. These findings underscore the importance of more in-depth investigations to elucidate the roles and mechanisms of these lncRNAs.

3. Conclusions

It is evident from emerging studies that lncRNAs regulate the fine balance between pro- and antiangiogenic factors, and that their deregulation may contribute to the transition from the dormant avascular tumour to an angiogenic malignant phenotype. Emerging studies have identified several lncRNAs as key regulators of molecules which drive the angiogenic switch, such as VEGF, MMP9, and TIE. While most angiogenesis regulating lncRNAs are upregulated in various cancers, a few of these transcripts which exhibit antiangiogenic activity are downregulated. Of note is that in a diverse array of cancers the expression patterns of these lncRNAs correlate with clinical outcome. The findings of these studies render such angiogenesis modulating transcripts as potential cancer biomarkers. Moreover, some of the lncRNAs are stable in body fluids and can be useful in non-invasive applications. However, future investigations should focus on the sensitivity and specificity of MALAT1 and H19 in cancer detection. Studies with larger samples sizes are required to determine the degree of diagnostic accuracy. Important promoters of tumour angiogenesis can serve as therapeutic targets, including MALAT1, TUG1, LNC00323-003, PVT1, and MIR503HG. Antisense oligonucleotides have been employed for the modulation of gene expression, and their approval for the treatment of patients opens avenues for further exploration in the clinical application of silencing or targeting proangiogenic lncRNAs such as TUG1 and PVT1. The targeting of MALAT1 with GapmeR has recently been shown to be effective in myeloma. There is a need to further elaborate possible drug delivery platforms that will enhance tumour tissue specific targeting to minimize the off-target effects commonly encountered with most anti-cancer treatments. Furthermore, the limitations of current studies on angiogenic lncRNAs is that they have focused on inhibiting vessel formation. On the other hand, it is well-known that tumour blood vessels are structurally and functionally abnormal, and hamper drug delivery.

This entry is adapted from the peer-reviewed paper 10.3390/genes13010152

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