Exo-circRNAs: a new paradigm for anticancer therapy.

CircRNAs, as new members of long noncoding RNAs, have been the focus of recent investigation. CircRNAs feature a closed continuous loop structure without 5'-3' polarity or a poly A tail. Many studies have reported the potential application of circRNAs in the clinic as new biomarkers and therapeutic targets in different diseases, especially for cancer. Additionally, the exosomes are important vehicles in cell-to-cell communication. And exo-circRNAs are circRNAs in exosomes which can be detected to provide additional evidence for conventional diagnostic methods and can be applied to suppress the malignant progress in cancer. In this review, we describe the biogenesis, characteristics, and functions of circRNAs and exosomes. Specifically, we present a comprehensive update of the promising role of exo-circRNAs in anticancer therapy.

The mechanism and function of circular RNAs in human diseases.

Circular RNAs (circRNAs) are a recently discovered form of RNA. Initially, circRNAs were believed to result from errors during the process of gene transcription. However, after further investigation, scientists suggested that circRNAs are of great biological significance. CircRNAs show stability, conservation, abundance, and tissue and stage specificity. They can also function as miRNA sponges, regulate gene expression, and interact with proteins to affect cell behavior. Emerging evidence has also demonstrated that circRNAs participate or show abnormal expression in diseases, including central nervous system diseases, cardiovascular diseases and cancers, indicating their marked potential in the prediction and prognosis of diseases and clinical treatment.

HIF signaling: A new propellant in bone regeneration.

Bone tissue destruction leads to severe pain, physical flaws, and loss of motility. Bone repair using biocompatible and osteo-inductive scaffolds is regarded as a viable and potential therapeutic approach. However, for large-scale bone regeneration, oxygen and nutrient supply have become limiting factors. Further, a considerable need exists for recruited cell activities and blood vessel growth. Hypoxia-inducible factor (HIF) signaling pathways induced by hypoxia are involved in angiogenesis and osteogenesis. As an important transcription factor, HIF-1 functions by modulating vital genes, such as VEGF, PDK1, and EPO, and is a crucial regulator that influences the final fate of bone regeneration. Collectively, to achieve better osteogenesis results, the in-depth molecular mechanisms that underpin the links between materials, cells, and HIF signaling pathways must be determined. This review aimed to provide an in-depth insight into recent progress in HIF-regulated bone regeneration. Hypoxia and cellular oxygen-sensing mechanisms and their correlations with osteogenesis were determined, and recent studies on hypoxia-inducing and hypoxia-mimicking strategies were briefly described. Finally, the potential applications of HIF signaling in bone regeneration were highlighted. This review provides theoretical support for establishing a novel and viable bone repair strategy in the clinic by harnessing HIF signaling.

Hypoxia inducible factor-1 signaling pathway in macrophage involved angiogenesis in materials-instructed osteo-induction.

Although osteo-inductive materials are regarded as promising candidates for critical-sized bone repair, their clinical application is limited by ambiguous mechanisms. The hypoxia-inducible factor (HIF)-1 signaling pathway, which responds to hypoxic conditions, is involved in both angiogenesis and osteogenesis. Strategies harnessing HIF-1 signaling to promote angiogenesis have been applied and have succeeded in repairing segmental bone defects. Meanwhile, macrophages have been shown to have important immunoregulatory effects on material-induced osteo-induction and correlate with HIF-1 activity. Thus, it is reasonable to assume that HIF-activated macrophages may also play important roles in the angiogenesis of material-induced osteo-induction. To verify this assumption, a classical type of osteo-inductive calcium phosphate (TCPs) was utilized. First, using RNA sequencing, we found that hypoxia activated the HIF signaling pathway in macrophages, which contributed to angiogenesis in TCPs. In addition, after treatment with a conditioned medium extracted from the co-culture system of macrophages and TCPs under hypoxic conditions, the migration and tube formation ability of human umbilical vein endothelial cells (HUVECs) significantly increased. In vivo, inhibition of HIF-1 or clearance of macrophages could result in impaired angiogenesis in TCPs. Finally, more blood vessels were formed in the TCPs group than in the control group. In conclusion, this study elucidated the vital role of the HIF signaling pathway in infiltrating macrophages during early vessel growth in material-induced osteo-induction. It is beneficial in advancing the exploration of the related mechanism and providing possible support for optimizing the applicability of osteo-inductive materials in bone repair.

Serial cellular events in bone formation initiated by calcium phosphate ceramics.

To better understand the biological mechanisms triggered by osteoinductive materials in vivo, we evaluated the timeline of cellular responses to osteoinductive materials subcutaneously implanted in FVB mice. More F4/80-positive macrophages were present in osteoinductive tri-CaP ceramic (TCP) with submicron surface topography (TCPs) than non-osteoinductive TCP with micron surface topography (TCPb) at week 1. Moreover, TCPs (but not TCPb) significantly enhanced osteoclastogenesis, and induced macrophages to polarize from M1 to M2 in the first week. The time sequence and relevance of macrophages and osteoclasts responses involved in bone formation was then evaluated through peri-implant injection of specific chemicals in mice implanted with osteoinductive TCPs. Day-1 injection of clodronate liposomes (LipClod) depleted macrophages, inhibited macrophage polarization to M2, blocked osteoclastogenesis and bone formation, while the day-6 injection was less effective. Anti-RANKL antibody (aRANKL) did not affect macrophage colonization but inhibited osteoclastogenesis. Injection of aRANKL before week 2 aborted bone formation in TCPs, while injection at week 4 partially inhibited bone formation. The overall data show that following ectopic implantation, osteoinductive materials allow macrophage colonization in hours to days, macrophage polarization to M2 in days (within 7 days), osteoclastogenesis in weeks (e.g. in 2 weeks) and bone formation thereafter (after 4 weeks). The serial cellular events verified herein bring a new insight on material-induced bone formation and pave the way to further explore the mechanisms triggered by osteoinductive materials. STATEMENT OF SIGNIFICANCE: A series of key cellular events triggered by osteoinductive calcium phosphate ceramic was revealed: macrophages colonized within hours to days, polarization of M2 macrophages occurred within 7 days, osteoclastogenesis mainly occurred in weeks (e.g. in 2 weeks) and bone formation finally arose thereafter (after 4 weeks). Moreover, such time sequence of cellular events was confirmed with specific chemicals (clodronate liposomes and anti-RANKL antibody). The findings verified herein bring a new insight on material-induced bone formation and pave the way to further explore the mechanisms triggered by osteoinductive materials.

[Development of precancerous lesions of oral mucous membrane diseases and oral cancer animal models].

Precancerous lesions of oral mucous membrane diseases and oral cancer are common diseases in developing countries, especially in South Asia. However, the cancerous mechanism remains unclear, and no efficient treatment and prognosis measure are currently available. Thus, precancerous lesions of the oral mucosa and oral cancer animal models must be identified to further understand their function. In this paper, we systematically review the development of oral mucosal precancerous lesions and oral cancer animal models by referring to related research.

PA28γ, an Accomplice to Malignant Cancer.

PA28γ is a nuclear activator of the 20S proteasome, which is involved in the regulation of several essential cellular processes and angiogenesis. Over the past 20 years, many amino acid sites and motifs have been proven to play important roles in the characteristic functions of PA28γ. The number of binding partners and validated cellular functions of PA28γ have increased, which has facilitated the clarification of its involvement in different biological events. PA28γ is involved in the progression of various diseases, and its aberrant overexpression in cancer is remarkable. Patients with low levels of PA28γ expression have a higher survival rate than those with high levels of PA28γ expression, as has been shown for a wide variety of tumors. The functions of PA28γ in cancer can be divided into five main categories: cell proliferation, cell apoptosis, metastasis and invasion, cell nuclear dynamics that have relevance to angiogenesis, and viral infection. In this review, we focus on the role of PA28γ in cancer, summarizing its aberrant expression, prooncogenic effects and underlying mechanisms in various cancers, and we highlight the possible cancer-related applications of PA28γ, such as its potential use in the diagnosis, targeted treatment and prognostic assessment of cancer.

[Research progress on circular RNA in oral squamous cell carcinoma].

Circular RNA, a non-coding RNA that forms a covalently closed continuous loop, exists widely in eukaryotic cells. The biogenesis and biological function of this type of RNA indicate that it can play a crucial role in diseases such as tumors, neural system diseases, and cardiovascular diseases; moreover, this RNA may have great potential use as a biomarker in these diseases. Oral squamous cell carcinoma (OSCC) is a common malignancy in oral surgery that is difficult to cure, metastasizes easily, and has poor prognosis. In this review, we summarize the loop-forming mechanisms and functions of circular RNA and describe the progress of current research in the development of oral cancer.

Noncoding RNAs in oral premalignant disorders and oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) has the highest mortality rate among all head and neck cancers and a relatively low five-year survival rate. Generally, the development of an oral mucosal malignancy represents a multistep process beginning with normal oral mucosa epithelium and culminating in OSCC after transitioning through intermediary oral premalignant disorders (OPMDs), during which dysplasia is often observed. Noncoding RNAs (ncRNAs) are RNAs that are not translated into proteins, but still can participate in regulating neoplastic cell behavior. Recently, data have emerged on the role of ncRNAs in the progression of oral mucosal malignant diseases, but the exact mechanisms through which ncRNAs are involved remain to be elucidated. CONCLUSIONS: Knowledge on ncRNAs has added an extra layer of complexity to our understanding of the malignant progression of oral mucosal diseases. The identification of ncRNAs in multiple body fluids as biomarkers may provide new diagnostic options that can be used for the diagnosis and prognosis of OPMDs and OSCC, respectively. Despite overall advances that have been made in cancer treatment, the treatment options for OPMDs and OSCC are still limited. Several studies have shown that ncRNA-based treatment regimens may hold promise as alternative methods for treating OPMDs and OSCC. The use of ncRNAs as therapeutic agents, including miR-155, miR-34 and lncRNA HOTAIR, appear promising.

PA28γ acts as a dual regulator of IL-6 and CCL2 and contributes to tumor angiogenesis in oral squamous cell carcinoma.

PA28γ promotes tumor development and progression and is suggested to play a role in tumor angiogenesis, but the molecular mechanisms have not been investigated. Here, we found that PA28γ enhanced the ability of OSCC cells to promote the migration, invasion, and tube formation of HUVECs and promoted tumor-induced angiogenesis in xenograft mice models in vivo. Then, a mechanism study revealed that the expression and secretion of IL-6 and CCL2 were dependent on PA28γ expression. Furthermore, blocking IL-6 or CCL2 or the transcription factor NF-κB induced the inhibition of tube formation in HUVECs co-cultured with PA28γ-overexpression OSCC cell supernatants. Moreover, we revealed that p-STAT3 and p-AKT, which are downstream of the IL-6 and CCL2 signaling axis, were downregulated in HUVECs co-cultured with the PA28γ-silenced supernatant and were upregulated with the PA28γ-overexpressing supernatant. In addition, IL-6, CCL2 and PA28γ expressions were correlated in a clinical OSCC cohort. Collectively, our study indicates that PA28γ contributes to tumor angiogenesis by regulating IL-6 and CCL2. PA28γ may be a novel therapeutic target as a dual regulator of IL-6 and CCL2 for treating PA28γ-positive OSCC.