Critical Roles of PIWIL1 in Human Tumors: Expression, Functions, Mechanisms, and Potential Clinical Implications.

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a class of small non-coding RNA molecules that are 24-31 nucleotides in length. PiRNAs are thought to bind to PIWI proteins (PIWL1-4, a subfamily of Argonaute proteins), forming piRNA/PIWI complexes that influence gene expression at the transcriptional or post-transcriptional levels. However, it has been recently reported that the interaction of PIWI proteins with piRNAs does not encompass the entire function of PIWI proteins in human tumor cells. PIWIL1 (also called HIWI) is specifically expressed in the testis but not in other normal tissues. In tumor tissues, PIWIL1 is frequently overexpressed in tumor tissues compared with normal tissues. Its high expression is closely correlated with adverse clinicopathological features and shorter patient survival. Upregulation of PIWIL1 drastically induces tumor cell proliferation, epithelial-mesenchymal transition (EMT), invasion, cancer stem-like properties, tumorigenesis, metastasis and chemoresistance, probably via piRNA-independent mechanisms. In this article, we summarize the current existing literature on PIWIL1 in human tumors, including its expression, biological functions and regulatory mechanisms, providing new insights into how the dysregulation of PIWIL1 contributes to tumor initiation, development and chemoresistance through diverse signaling pathways. We also discuss the most recent findings on the potential clinical applications of PIWIL1 in cancer diagnosis and treatment.

PD-L1 Is a Tumor Suppressor in Aggressive Endometrial Cancer Cells and Its Expression Is Regulated by miR-216a and lncRNA MEG3.

BACKGROUND: Poorly differentiated endometrioid adenocarcinoma and serous adenocarcinoma represent an aggressive subtype of endometrial cancer (EC). Programmed death-ligand-1 (PD-L1) was known to exhibit a tumor cell-intrinsic function in mediating immune-independent tumor progression. However, the functional relevance of tumor cell-intrinsic PD-L1 expression in aggressive EC cells and the mechanisms regulating its expression remain unknown. METHODS: PD-L1 expression in 65 EC tissues and 18 normal endometrium samples was analyzed using immunohistochemical staining. The effects of PD-L1 on aggressive EC cell growth, migration and invasion were investigated by cell functional assays. Luciferase reporter assays were used to reveal the microRNA-216a (miR-216a)-dependent mechanism modulating the expression of PD-L1. RESULTS: Positive PD-L1 expression was identified in 84% of benign cases but only in 12% of the EC samples, and the staining levels of PD-L1 in EC tissues were significantly lower than those in the normal tissues. Higher PD-L1 expression predicts favorable survival in EC. Ectopic expression of PD-L1 in aggressive EC cells results in decreased cell proliferation and the loss of mesenchymal phenotypes. Mechanistically, PD-L1 exerts the anti-tumor effects by downregulating MCL-1 expression. We found that PD-L1 levels in aggressive EC cells are regulated by miR-216a, which directly targets PD-L1. We further identified a mechanism whereby the long non-coding RNA MEG3 represses the expression of miR-216a, thereby leading to increased PD-L1 expression and significant inhibition of cell migration and invasion. CONCLUSION: These results reveal an unappreciated tumor cell-intrinsic role for PD-L1 as a tumor suppressor in aggressive EC cells, and identify MEG3 and miR-216a as upstream regulators of PD-L1.

The Expression, Functions and Mechanisms of Circular RNAs in Gynecological Cancers.

Circular RNAs (circRNAs) are covalently closed, endogenous non-coding RNAs and certain circRNAs are linked to human tumors. Owing to their circular form, circRNAs are protected from degradation by exonucleases, and therefore, they are more stable than linear RNAs. Many circRNAs have been shown to sponge microRNAs, interact with RNA-binding proteins, regulate gene transcription, and be translated into proteins. Mounting evidence suggests that circRNAs are dysregulated in cancer tissues and can mediate various signaling pathways, thus affecting tumorigenesis, metastasis, and remodeling of the tumor microenvironment. First, we review the characteristics, biogenesis, and biological functions of circRNAs, and describe various mechanistic models of circRNAs. Then, we provide a systematic overview of the functional roles of circRNAs in gynecological cancers. Finally, we describe the potential future applications of circRNAs as biomarkers for prognostic stratification and as therapeutic targets in gynecological cancers. Although the function of most circRNAs remains elusive, some individual circRNAs have biologically relevant functions in cervical cancer, ovarian cancer, and endometrial cancer. Certain circRNAs have the potential to serve as biomarkers and therapeutic targets in gynecological cancers.

MicroRNA-361-Mediated Inhibition of HSP90 Expression and EMT in Cervical Cancer Is Counteracted by Oncogenic lncRNA NEAT1.

Epithelial-mesenchymal transition (EMT) is a key process contributing to cervical cancer (CC) metastasis, and microRNAs (miRNAs) modulate the expression of genes implicated in EMT. However, the accurate role of miR-361 in CC-associated EMT and the mechanisms underlying its function in CC remains largely unknown. The functional roles of miR-361 in CC cells were explored by a series of cell functional assays. Luciferase reporter assays were used to demonstrate the potential interaction between miR-361, HSP90, and long non-coding RNA (lncRNA) NEAT1. We detected a reduction of miR-361 expression in CC tissues compared with normal tissues, and miR-361 overexpression inhibited invasion and EMT phenotypes of CC cells by directly targeting a key EMT activator HSP90. Additionally, we detected significantly higher levels of HSP90 in CC tissues compared with normal tissues, and high expression of HSP90 predicted a poorer prognosis. We further identified NEAT1 as a significantly upregulated lncRNA in CC tissues and high expression of NEAT1 was associated with worse survival in CC patients. NEAT1 directly repressed miR-361 expression and played an oncogenic role in CC cell invasion and sphere formation. Conclusions: These results demonstrated that miR-361 directly targets HSP90 to inhibit the invasion and EMT features, and NEAT1 functions as an oncogenic lncRNA that suppresses miR-361 expression and induces EMT and sphere formation in CC cells, thus providing critical insights into the molecular pathways operating in this malignancy.

MicroRNA-361: A Multifaceted Player Regulating Tumor Aggressiveness and Tumor Microenvironment Formation.

MicroRNA-361-5p (miR-361) expression frequently decreases or is lost in different types of cancers, and contributes to tumor suppression by repressing the expression of its target genes implicated in tumor growth, epithelial-to-mesenchymal transition (EMT), metastasis, drug resistance, glycolysis, angiogenesis, and inflammation. Here, we review the expression pattern of miR-361 in human tumors, describe the mechanisms responsible for its dysregulation, and discuss how miR-361 modulates the aggressive properties of tumor cells and alter the tumor microenvironment by acting as a novel tumor suppressor. Furthermore, we describe its potentials as a promising diagnostic or prognostic biomarker for cancers and a promising target for therapeutic development.

Long noncoding RNA NEAT1 drives aggressive endometrial cancer progression via miR-361-regulated networks involving STAT3 and tumor microenvironment-related genes.

BACKGROUND: High-grade endometrioid and serous endometrial cancers (ECs) are an aggressive subtype of ECs without effective therapies. The reciprocal communication between tumor cells and their surrounding microenvironment drives tumor progression. Long noncoding RNAs (lncRNAs) are key mediators of tumorigenesis and metastasis. However, little is known about the role of lncRNAs in aggressive EC progression and tumor microenvironment remodeling. METHODS: We performed an array-based lncRNA analysis of a parental HEC-50 EC cell population and derivatives with highly invasive, sphere-forming, and paclitaxel (TX)-resistant characteristics. We characterized the roles of the lncRNA NEAT1 in mediating aggressive EC progression in vitro and in vivo and explored the molecular events downstream of NEAT1. RESULTS: We identified 10 lncRNAs with upregulated expression (NEAT1, H19, PVT1, UCA1, MIR7-3HG, SNHG16, HULC, RMST, BCAR4 and LINC00152) and 10 lncRNAs with downregulated expression (MEG3, GAS5, DIO3OS, MIR155HG, LINC00261, FENDRR, MIAT, TMEM161B-AS1, HAND2-AS1 and NBR2) in the highly invasive, sphere-forming and TX-resistant derivatives. NEAT1 expression was markedly upregulated in early-stage EC tissue samples, and high NEAT1 expression predicted a poor prognosis. Inhibiting NEAT1 expression with small hairpin RNAs (shRNAs) diminished cellular proliferation, invasion, sphere formation, and xenograft tumor growth and improved TX response in aggressive EC cells. We showed that NEAT1 functions as an oncogenic sponge for the tumor suppressor microRNA-361 (miR-361), which suppresses proliferation, invasion, sphere formation and TX resistance by directly targeting the oncogene STAT3. Furthermore, miR-361 also suppressed the expression of multiple prometastatic genes and tumor microenvironment-related genes, including MEF2D, ROCK1, WNT7A, VEGF-A, PDE4B, and KPNA4. CONCLUSIONS: NEAT1 initiates a miR-361-mediated network to drive aggressive EC progression. These data support a rationale for inhibiting NEAT1 signaling as a potential therapeutic strategy for overcoming aggressive EC progression and chemoresistance.