Molecular Landscape of LncRNAs in Prostate Cancer: A focus on pathways and therapeutic targets for intervention

Abstract

Background: One of the most malignant tumors in men is prostate cancer that is still incurable due to its heterogenous and progressive natures. Genetic and epigenetic changes play significant roles in its development. The RNA molecules with more than 200 nucleotides in length are known as lncRNAs and these epigenetic factors do not encode protein. They regulate gene expression at transcriptional, post-transcriptional and epigenetic levels. LncRNAs play vital biological functions in cells and in pathological events, hence their expression undergoes dysregulation.

Aim of review: The role of epigenetic alterations in prostate cancer development are emphasized here. Therefore, lncRNAs were chosen for this purpose and their expression level and interaction with other signaling networks in prostate cancer progression were examined.

Key scientific concepts of review: The aberrant expression of lncRNAs in prostate cancer has been well-documented and progression rate of tumor cells are regulated via affecting STAT3, NF-κB, Wnt, PI3K/Akt and PTEN, among other molecular pathways. Furthermore, lncRNAs regulate radio-resistance and chemo-resistance features of prostate tumor cells. Overexpression of tumor-promoting lncRNAs such as HOXD-AS1 and CCAT1 can result in drug resistance. Besides, lncRNAs can induce immune evasion of prostate cancer via upregulating PD-1. Pharmacological compounds such as quercetin and curcumin have been applied for targeting lncRNAs. Furthermore, siRNA tool can reduce expression of lncRNAs thereby suppressing prostate cancer progression. Prognosis and diagnosis of prostate tumor at clinical course can be evaluated by lncRNAs. The expression level of exosomal lncRNAs such as lncRNA-p21 can be investigated in serum of prostate cancer patients as a reliable biomarker.

Keywords: Drug resistance; Exosome; Immune evasion; Long non-coding RNA (lncRNA); MicroRNA; Prostate cancer.

Fig. 1

An overview of lncRNA function in affecting downstream targets. RNA polymerase II is involved in generation of lncRNAs and they participate in various functions in cells such as miRNA sponge, protein interaction and chromatin modification

Fig. 2

The lncRNAs regulating miRNAs in prostate cancer. LncRNAs reduce the expression level of target miRNAs via sponging. The tumor progression including proliferation and invasion, as well as drug resistance are modulated by lncRNA/miRNA axis in prostate cancer. Regulating expression level of lncRNAs or miRNAs is beneficial in impairing progression of prostate cancer cells

Fig. 3

LncRNAs in regulation of other molecular pathways in prostate cancer. PTEN, STAT3, mTOR and EZH2 are main molecular pathways involved in regulating prostate cancer progression. LncRNAs can directly interact with aforementioned factors or target miRNAs in affecting their expression level

Fig. 4

Role of lncRNAs in proliferation and metastasis of prostate cancer cells. EMT is responsible for increasing migration and invasion of prostate cancer cells. LncRNA SNH17 and PCAT7 are among the lncRNAs inducing EMT in increasing prostate cancer metastasis. Apoptosis induction and transfer of glucose into prostate cancer cells (GLUT1) are also modulated by lncRNAs

Fig. 5

The lncRNAs regulate therapy response and immune system interactions in prostate cancer. The overexpression of tumor-promoting lncRNAs lead to drug resistance. Furthermore, overexpression of PD-L1 by lncRNAs can lead to immune escape in prostate cancer

Fig. 6

Therapeutic targeting of lncRNAs in prostate cancer. Anti-tumor compounds such as curcumin and siRNA can be used to decrease expression level of tumor-promoting lncRNAs in impairing progression of prostate cancer cells