Can Guo

Role of tumor microenvironment in tumorigenesis

Tumorigenesis is a complex and dynamic process, consisting of three stages: initiation, progression, and metastasis. Tumors are encircled by extracellular matrix (ECM) and stromal cells, and the physiological state of the tumor microenvironment (TME) is closely connected to every step of tumorigenesis. Evidence suggests that the vital components of the TME are fibroblasts and myofibroblasts, neuroendocrine cells, adipose cells, immune and inflammatory cells, the blood and lymphatic vascular networks, and ECM. This manuscript, based on the current studies of the TME, offers a more comprehensive overview of the primary functions of each component of the TME in cancer initiation, progression, and invasion. The manuscript also includes primary therapeutic targeting markers for each player, which may be helpful in treating tumors.

Epstein-Barr virus-encoded miR-BART6-3p inhibits cancer cell metastasis and invasion by targeting long non-coding RNA LOC553103

Epstein-Barr virus (EBV) infection is causatively related to a variety of human cancers, including nasopharyngeal carcinoma (NPC) and gastric cancer (GC). EBV encodes 44 mature miRNAs, a number of which have been proven to promote carcinogenesis by targeting host genes or self-viral genes. However, in this study, we found that an EBV-encoded microRNA, termed EBV-miR-BART6-3p, inhibited EBV-associated cancer cell migration and invasion including NPC and GC by reversing the epithelial–mesenchymal transition (EMT) process. Using microarray analysis, we identified and validated that a novel long non-coding RNA (lncRNA) LOC553103 was downregulated by EBV-miR-BART6-3p, and LOC553103 knockdown by specific siRNAs phenocopied the effect of EBV-miR-BART6-3p, while LOC553103 overexpression promoted cancer cell migration and invasion to facilitate EMT. In conclusion, we determined that EBV-miR-BART6-3p, a microRNA encoded by oncogenic EBV, inhibited EBV-associated cancer cell migration and invasion by targeting and downregulating a novel lncRNA LOC553103. Thus, our study presents an unreported mechanism underlying EBV infection in EBV-associated cancer carcinogenesis, and provides a potential novel diagnosis and treatment biomarker for NPC and other EBV-related cancers.

Upregulated long non-coding RNA LINC00152 expression is associated with progression and poor prognosis of tongue squamous cell carcinoma

Altered expression of long non-coding RNAs (lncRNAs) associated with human carcinogenesis and might be used as diagnosis and prognosis biomarkers. However, the expression of lncRNAs in tongue squamous cell carcinoma (TSCC) and their relevance on the diagnosis, progression and prognosis of TSCC have not been thoroughly elucidated. To discover novel TSCC-related lncRNAs, we analyzed the lncRNA expression patterns in two sets of previously published TSCC gene expression profile data (GSE30784 and GSE9844), and found that long intergenic non-coding RNA 152 (LINC00152) was significantly upregulated in TSCC samples. We then detected LINC00152 expression in two other cohorts of TSCC samples. Quantitative Real time PCR (qRT-PCR) results indicated that LINC00152 was highly expressed in 15 primary TSCC biopsies when compared with 14 adjacent non-tumor tongue squamous cell epithelium samples. The expression of LINC00152 was also measured in 182 paraffin-embedded human TSCC tissues by in situ hybridization, increased expression of LINC00152 was significantly correlated with TSCC progression, such as T stage (p = 0.009), N stage (p = 0.036), TNM stage (p = 0.017), and associated with relapse (p < 0.001), and invasion (p < 0.001). Kaplan-Meier analysis demonstrated that increased LINC00152 expression contributed to both poor overall survival (p = 0.006) and disease-free survival (p = 0.007) of TSCC patients. These findings suggest that LINC00152 might serve as a potential biomarker for early detection and prognosis prediction of TSCC.

Co-expression of AFAP1-AS1 and PD-1 predicts poor prognosis in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) carries a high potential for metastasis and immune escape, with a great risk of relapse after primary treatment. Through analysis of whole genome expression profiling data in NPC samples, we found that the expression of a long non-coding RNA (lncRNA), actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1), is significantly correlated with the immune escape marker programmed death 1 (PD-1). We therefore assessed the expression of AFAP1-AS1 and PD-1 in a cohort of 96 paraffin-embedded NPC samples and confirmed that AFAP1-AS1 and PD-1 are co-expressed in infiltrating lymphocytes in NPC tissue. Moreover, patients with high expression of AFAP1-AS1 or PD-1 in infiltrating lymphocytes were more prone to distant metastasis, and NPC patients with positive expression of both AFAP1-AS1 and PD-1 had the poorest prognosis. This study suggests that AFAP1-AS1 and PD-1 may be potential therapeutic targets in NPC and that patients with co-expression of AFAP1-AS1 and PD-1 may be ideal candidates for future clinical trials of anti-PD-1 immune therapy.

Overexpression long non-coding RNA LINC00673 is associated with poor prognosis and promotes invasion and metastasis in tongue squamous cell carcinoma

Long non-coding RNAs (lncRNAs) associated with the tumorigenesis of human cancers. However, the relevance of lncRNAs in tongue squamous cell carcinoma (TSCC) is still unclear. To discover novel TSCC-related lncRNAs, we analyzed the lncRNA expression patterns in two sets of TSCC gene expression profile data, and found that long intergenic non-coding RNA 673 (LINC00673) was significantly upregulated in TSCC samples. Then we examined LINC00673 expression in 202 TSCC tissue specimens, LINC00673 is highly expressed in a significant proportion of human TSCC biopsies and correlates with poor prognosis. Knockdown LINC00673 significantly inhibited the cell invasion and migration capability in TSCC cells. Our findings suggest that LINC00673 may play an essential role in TSCC progression and might serve as a potential biomarker for early detection and prognosis prediction of TSCC.

Genome-wide analysis of 18 Epstein-Barr viruses isolated from primary nasopharyngeal carcinoma biopsy specimens

ABSTRACT Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that is highly prevalent in almost all human populations and is associated with many human cancers, such as nasopharyngeal carcinoma (NPC), Hodgkins disease, and gastric carcinoma. However, in these EBV-associated cancers, only NPC exhibits remarkable ethnic and geographic distribution. We hypothesized that EBV genomic variations might contribute to the pathogenesis of different human cancers in different geographic areas. In this study, we collected 18 NPC biopsy specimens from the Hunan Province in southern China and de novo assembled 18 NPC biopsy specimen-derived EBV (NPC-EBV) genomes, designated HN1 to HN18. This was achieved through target enrichment of EBV DNA by hybridization, followed by next-generation sequencing, to reveal sequence diversity. These EBV genomes harbored 20,570 variations totally, including 20,328 substitutions, 88 insertions, and 154 deletions, compared to the EBV reference genome. Phylogenetic analysis revealed that all NPC-EBV genomes were distinct from other EBV genomes. Furthermore, HN1 to HN18 had some nonsynonymous variations in EBV genes including genes encoding latent, early lytic, and tegument proteins, such as substitutions within transmembrane domains 1 and 3 of LMP1, FoP_duplication, and zf-AD domains of ENBA1, in addition to aberrations in noncoding regions, especially in BamHI A rightward transcript microRNAs. These variations might have potential biological significance. In conclusion, we reported a genome-wide view of sequence variation in EBV isolated from primary NPC biopsy specimens obtained from the Hunan Province. This might contribute to further understanding of how genomic variations contribute to carcinogenesis, which would impact the treatment of EBV-associated cancer. IMPORTANCE Nasopharyngeal carcinoma (NPC) is highly associated with Epstein-Barr virus (EBV) infection and exhibits remarkable ethnic and geographic distribution. Hunan Province in southern China has a high incidence rate of NPCs. Here, we report 18 novel EBV genome sequences from viruses isolated from primary NPC biopsy specimens in this region, revealing whole-genome sequence diversity.

LncRNAs regulate cancer metastasis via binding to functional proteins

Cancer is one of the leading causes of death worldwide, and metastasis is a crucial characteristic of malignancy. Recent studies have shown that lncRNAs play an important role in regulating cancer metastasis through various molecular mechanisms. We briefly summarize four known molecular functions of lncRNAs, including their role as a signal, decoy, guide and scaffold. No matter which pattern lncRNAs follow to carry out their functions, the proteins that lncRNAs bind to are important for them to exhibit their gene-regulating properties. We further illustrate that lncRNAs regulate the localization, stabilization or modification of their binding proteins to realize the binding role of lncRNAs. In this review, we focus on the interactions between lncRNAs and their binding proteins; moreover, we focus on the mechanisms of the collaborative work of lncRNAs and their binding proteins in cancer metastasis, thus evaluating the potential of lncRNAs as prospective novel therapeutic targets in cancer.

High Expression of LINC01420 indicates an unfavorable prognosis and modulates cell migration and invasion in nasopharyngeal carcinoma.

Recent studies demonstrated that long non-coding RNAs (lncRNAs) deregulated in many cancer tissues including nasopharyngeal carcinoma (NPC) and had critical roles in cancer progression and metastasis. In this study, we aimed to assess a lncRNA LINC01420 expression in NPC and explore its role in NPC pathogenesis. Our research revealed that the expression level of LINC01420 in NPC tissues were higher than nasopharyngeal epithelial (NPE) tissues. Moreover, NPC patients with high LINC01420 expression level showed poor overall survival. Knockdown LINC01420 inhibited NPC cell migration and invasion in vitro. In summary, LINC01420 may play a critical role in NPC progression and may serve as a potential prognostic biomarker in NPC patients.

Long non-coding RNA AFAP1-AS1 is a novel biomarker in various cancers: a systematic review and meta-analysis based on the literature and GEO datasets

Background Growing evidence indicates that AFAP1-AS1 plays an important role in various cancers, suggesting that it might be a potential cancer biomarker. Materials and Methods A meta-analysis was performed using microarray data obtained via the Affymetrix Human Genome U133 Plus 2.0 platform (found in the GEO database) and data obtained through a systematic search of PubMed and Web of Science. The pooled odds ratio (OR) and hazard ratio (HR) with 95% CI (confidence interval) were used to judge the value of biomarkers. Results A total of 30 studies were included in this meta-analysis, comprising a total of 3573 patients. AFAP1-AS1 was significantly linked with overall survival (OS) (HR = 1.58; 95% CI: 1.12–2.23) and recurrence-free survival (RFS) (HR = 2.32, 95% CI: 1.68–3.19). We found that AFAP1-AS1 was a risk factor in the prognoses of lung cancer (pooled HR: 1.54; 95% CI: 1.01–2.34), digestive system cancer (pooled HR: 1.87; 95% CI: 1.45–2.41) and nasopharyngeal carcinoma (HR: 11.82; 95% CI: 5.09–27.46). AFAP1-AS1 was also a risk factor for RFS in breast cancer (pooled HR = 2.90; 95% CI: 1.69–4.98), as well as TNM stage in both esophageal cancer (pooled OR = 1.90; 95% CI: 1.01–3.57) and colorectal cancer (OR = 6.72; 95% CI: 1.92–23.58). AFAP1-AS1 was significantly associated with lymph node metastasis in clear cell carcinoma (OR = 5.04; 95% CI: 2.36–10.78) and distant metastasis in pancreatic cancer (OR = 11.64; 95% CI: 2.13–63.78). Conclusions AFAP1-AS1 can serve as a novel molecular marker predicting tumor progression, patient prognosis and lymph node metastasis in different types of cancers.

LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis

Some of the key steps in cancer metastasis are the migration and invasion of tumor cells; these processes require rearrangement of the cytoskeleton. Actin filaments, microtubules, and intermediate filaments involved in the formation of cytoskeletal structures, such as stress fibers and pseudopodia, promote the invasion and metastasis of tumor cells. Therefore, it is important to explore the mechanisms underlying cytoskeletal regulation. The ras homolog family (Rho) and Rho-associated coiled-coil containing protein serine/threonine kinase (ROCK) signaling pathway is involved in the regulation of the cytoskeleton. Moreover, long noncoding RNAs (lncRNAs) have essential roles in tumor migration and guide gene regulation during cancer progression. LncRNAs can regulate the cytoskeleton directly or may influence the cytoskeleton via Rho/ROCK signaling during tumor migration. In this review, we focus on the regulatory association between lncRNAs and the cytoskeleton and discuss the pathways and mechanisms involved in the regulation of cancer metastasis.