lncRNA Biomarkers of Glioblastoma Multiforme.

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood.

Alteration in the expression of long non-coding RNAs in the circulation of migraineurs.

BACKGROUND: Current studies have shown emerging roles of lncRNAs in the pathobiology of neuropathic pain and migraine. METHODS: We have chosen five lncRNAs, namely, PVT1, DSCAM-AS, MEG3, LINC-ROR, and SPRY4-IT1 for assessment of their expression in the circulation of migraineurs. RESULTS: Expressions of PVT1 and MEG3 were higher in total migraineurs and both subgroups compared with controls (P < 0.0001). Meanwhile, expression of both lncRNA was higher in migraineurs with aura versus migraineurs without aura (P value < 0.0001 and = 0.01, respectively). Expression of DSCAM-AS1 was not different between any groups of patients compared with controls. Expression of LINC-ROR was elevated in total patients and patients with aura compared with controls (P value = 0.0002 and < 0.0001, respectively). It was also over-expressed in migraineurs with aura vs. migraineurs without aura (P = 0.01). Finally, expression of SPRY4-IT1 was higher in total patients and patients without aura compared with migraine-free persons (P values < 0.0001). Expressions of five mentioned lncRNAs were correlated in almost all study groups. In patients without aura, correlations were significant only for two pairs (SPRY4-IT1/PVT1 and SPRY4-IT1/DSCAM-AS1). PVT1 and MEG3 had the appropriate AUC, sensitivity and specificity values for separation of total migraineurs and both groups of patients from controls. The highest AUC value was reported for PVT1 in separation of migraineurs with aura from healthy controls (AUC = 0.98). CONCLUSION: Cumulatively, our study shows evidence for deregulation of lncRNAs in migraineurs.

Synergistic anticancer effects of co-delivery of linc-RoR siRNA and curcumin using polyamidoamine dendrimers against breast cancer.

Breast cancer resistance to chemotherapy necessitates novel combination therapeutic approaches. Linc-RoR is a long intergenic noncoding RNA that regulates stem cell differentiation and promotes metastasis and invasion in breast cancer. Herein, we report a dual delivery system employing polyamidoamine dendrimers to co-administer the natural compound curcumin and linc-RoR siRNA for breast cancer treatment. Polyamidoamine dendrimers efficiently encapsulated curcumin and formed complexes with linc-RoR siRNA at an optimal N/P ratio. In MCF-7 breast cancer cells, the dendriplexes were effectively internalized and the combination treatment synergistically enhanced cytotoxicity, arresting the cell cycle at the G1 phase and inducing apoptosis. Linc-RoR gene expression was also significantly downregulated. Individual treatments showed lower efficacy, indicating synergism between components. Mechanistic studies are warranted to define the molecular underpinnings of this synergistic interaction. Our findings suggest dual delivery of linc-RoR siRNA and curcumin via dendrimers merits further exploration as a personalized therapeutic approach for overcoming breast cancer resistance.

Linc-ROR inhibits NK cell-killing activity by promoting RXRA ubiquitination and reducing MICB expression in gastric cancer patients.

Linc-ROR plays an important role in gastric cancer (GC) development and progression. This study sought to determine how the aberrant expression of Linc-ROR impacts GC progression and immune evasion, and to identify new targets for GC therapy. GC cells overexpressing Linc-ROR and GSAGS cells were cocultured with NK-92 cells, respectively, and Linc-ROR expression was determined using reverse transcription polymerase chain reaction. Linc-ROR overexpression experiments were used to measure the expression of MICB, a tumor protein that is recognized by natural killer (NK) cells. Bioinformatics analysis identified retinoid X receptor α (RXRA) and YY1 as MICB-specific transcription factors. Cotransfection and ubiquitinated drug experiments found that Linc-ROR promoted the ubiquitination and degradation of RXRA. Linc-ROR was upregulated in GC tissue and high expression was associated with tumor escape from NK-92 cell-mediated immunity. Linc-ROR overexpression inhibited the expression of MICB on the cell surface by degrading RXRA. These findings indicate that Linc-ROR promotes the binding of RXRA and E3 ligase UBE4B, reducing RXRA and MICB expression, and limiting NK cell-killing activity. Linc-ROR is a critical long noncoding RNA with a tumor-promoting function in GC and thus may serve as a potential therapeutic target.

Linc-ROR Regulates POU5F1 and SOX2 by Competitively Binding miR-145-5p to Affect the Proliferation and Migration of Gastric Cancer Cells.

Gastric cancer is the third leading cause of cancer-related deaths worldwide, and research on gastric cancer pathogenesis is fundamental. Long intergenic non-coding RNAs (lincRNAs) control cancer initiation and progression through several mechanisms, with the competitive endogenous RNA (ceRNA) regulatory network being the most common. In this study, in situ hybridization revealed that long intergenic non-protein coding RNA-regulator of reprogramming (linc-ROR) was highly expressed in gastric cancer cells and was mainly cytoplasmic-positive. Cell counting kit-8 (CCK-8), plate colony formation, wound healing, and Transwell assay revealed that linc-ROR knockdown impedes the growth, proliferation, and migration of gastric cancer cells, while linc-ROR overexpression promoted gastric cancer cell growth, migration, and colony formation ability. Combined with previous studies, the molecular mechanism axis of linc-ROR/miR-145-5-5p/POU5F1/SOX2 was verified. The expression of linc-ROR knockdown significantly suppressed the protein expression of POU5F1 and SOX2. Co-transfection with linc-ROR siRNA reverses the carcinogenic effect of the miR-145-5p inhibitor on gastric cancer cell proliferation, cloning, and migration. These findings lay a foundation for developing novel targets for gastric cancer treatment.

Linc-ROR Promotes EMT by Targeting miR-204-5p/SMAD4 in Endometriosis.

Endometriosis (EMs) is a systemic and chronic disease with cancer-like feature, namely, distant implantation, which caused heavy healthy burden of nearly 200 million females. LncRNAs have been proved as new modulators in epithelial-mesenchymal transition (EMT) and EMs. Quantitative real-time PCR was conducted to measure the expression level of long intergenic non-protein coding RNA, regulator of reprogramming (Linc-ROR), and miR-204-5p in ectopic endometrium (n = 25), eutopic endometrium (n = 20), and natural control endometrium (n = 22). Overexpression of Linc-ROR, knockdown or overexpression of miR-204-5p in End1/E6E7 and Ishikawa cells, was conducted to detect the function of Linc-ROR and miR-204-5p in EMs. Furthermore, luciferase reports were used to confirm the combination of Linc-ROR and miR-204-5p and the combination between miR-204-5p and SMAD4. Cell-Counting Kit-8, EdU assay, transwell assays, and Western blotting were used to detect the function of Linc-ROR and miR-204-5p in EMs cancer-like behaviors and EMT process. Linc-ROR was up-regulated in ectopic endometrium. Overexpressed Linc-ROR promotes cell proliferation, invasion, and EMT process. Linc-ROR regulated the EMT process, cellular proliferation, and invasion of EMs via binding to miR-204-5p. In addition, overexpression of Linc-ROR up-regulated SMAD4, a target protein of miR-204-5p, with which regulated EMT process and cancer-like behaviors in EMs together. Linc-ROR/miR-204-5p/SMAD4 axis plays a vital role in regulation EMT process in EMs, which might become a novel therapeutic targets and powerful biomarkers in EMs therapy.

A review on the importance of LINC-ROR in human disorders.

Long Intergenic Non-Protein Coding RNA, Regulator Of Reprogramming (LINC-ROR) is a long non-coding RNA with diverse physiological functions. The gene encoding this transcript resides on 18q21.31. Expression levels of LINC-ROR have been reported to be dysregulated in patients with diverse disorders, including cancer, autoimmune disorders and neurodegenerative and neurodevelopmental disorders. Moreover, polymorphisms within this lncRNA have been shown to be associated with a variety of disorders, such as some kinds of cancer and some aspects of systemic lupus erythematous. Abnormal expression of LINC-ROR in some other human disorders is not yet understood. Emerging evidence suggests that LINC-ROR exerts pivotal roles in most types of human disorders as an oncogene. Differentially expressed LINC-ROR contributes in the development of diseases by changing the expression of genes that control the cell cycle. It can also exert its role by affecting the activity of some cancer-related signaling pathways and sponging tumor suppressor miRNAs. Expanding our understanding of LINC-ROR functions will pave the way for developing efficient therapeutic strategies against cancer and related disorders. The current review aims at providing a concise overview of the role of LINC-ROR in diverse human disorders through providing a summary of association studies and expression assays.

Functional Relevance of the Long Intergenic Non-Coding RNA Regulator of Reprogramming (Linc-ROR) in Cancer Proliferation, Metastasis, and Drug Resistance.

Cancer is responsible for more than 10 million deaths every year. Metastasis and drug resistance lead to a poor survival rate and are a major therapeutic challenge. Substantial evidence demonstrates that an increasing number of long non-coding RNAs are dysregulated in cancer, including the long intergenic non-coding RNA, regulator of reprogramming (linc-ROR), which mostly exerts its role as an onco-lncRNA acting as a competing endogenous RNA that sequesters micro RNAs. Although the properties of linc-ROR in relation to some cancers have been reviewed in the past, active research appends evidence constantly to a better comprehension of the role of linc-ROR in different stages of cancer. Moreover, the molecular details and some recent papers have been omitted or partially reported, thus the importance of this review aimed to contribute to the up-to-date understanding of linc-ROR and its implication in cancer tumorigenesis, progression, metastasis, and chemoresistance. As the involvement of linc-ROR in cancer is elucidated, an improvement in diagnostic and prognostic tools could promote and advance in targeted and specific therapies in precision oncology.

Linc-ROR drive adriamycin resistance by targeting AP-2α/Wnt/ß-catenin axis in hepatocellular carcinoma.

Adriamycin is widely used as a chemotherapeutic strategy for advanced hepatocellular carcinoma (HCC). However, the clinical response was disappointing because of the acquired drug resistance with long-term usage. Revealing the underlying mechanism could provide promising therapeutics for the drug-resistant patients. The recently identified linc-ROR (long intergenic non-protein-coding RNA, regulator of reprogramming) has been found to be an oncogene in various cancers, and it also demonstrated to mediate drug resistance and metastasis. We thereby wonder whether this lincRNA could mediate adriamycin chemoresistance in HCC. In this study, linc-ROR was found to be upregulated in adriamycin-resistant HCC cells. And its overexpression accelerated epithelial-mesenchymal transition (EMT) program and adriamycin resistance. Conversely, its silence suppressed EMT and made HCC cells sensitize to adriamycin in vitro and in vivo. Further investigation revealed that linc-ROR physically interacted with AP-2α, mediated its stability by a post-translational modification manner, and sequentially activated Wnt/ß-catenin pathway. Furthermore, linc-ROR expression was positively associated with ß-catenin expression in human clinical specimens. Taken together, linc-ROR promoted tumorigenesis and adriamycin resistance in HCC via a linc-ROR/AP-2α/Wnt/ß-catenin axis, which could be developed as a potential therapeutic target for the adriamycin-resistant patients.

SOX2-Induced Linc-ROR Upregulation Inhibits Gastric Carcinoma Cell Proliferation and Metastasis Via the miR-580-3p/ANXA10 Pathway.

Previous studies have proven that long intergenic non-coding RNA regulator of reprogramming (Linc-ROR) plays opposing roles in different cancer types. This work intended to investigate its functions and underlying mechanisms in gastric carcinoma (GCa) progression. RT-qPCR was utilized for gene expression measurement. GCa cell viability, apoptosis, migration, and invasion were detected by functional assays, including CCK-8, flow cytometry, and Transwell assays. ChIP assay and Dual-luciferase reporter assay were utilized to affirm the associations between genes. Linc-ROR expression dramatically declined in GCa tissues and cell lines. Linc-ROR upregulation suppressed GCa cell proliferation, migration, and invasion but accelerated GCa cell apoptosis. As for Linc-ROR-associated molecular mechanisms in GCa, SOX2 associated with Linc-ROR promoter region to activate Linc-ROR transcription in GCa cells; Linc-ROR upregulated ANXA10 level in GCa cells by competitively binding to miR-580-3p. As revealed by rescue assays, Linc-ROR-induced inhibition on malignant biological behaviors of GCa cells could be partially abated by ANXA10 deletion or miR-580-3p upregulation. SOX2-activated Linc-ROR serves as a cancer suppressor to restrain GCa progression in vitro via the miR-580-3p/ANXA10 pathway, suggesting a promising diagnostic and therapeutic target for GCa patients.

The roles of Linc-ROR in the regulation of cancer stem cells.

Cancer stem cells (CSCs) are considered to be a kind of tumor cell population characterized by self-renewal, easy to metastasize and drug resistance, which play an indispensable role in the occurrence, development, metastasis and drug resistance of tumors, and their existence is an important reason for high metastasis and recurrence of tumors. Long non-coding RNAs (LncRNAs), which are more than 200 nucleotides in length, have a close relationship with the malignant progression of cancer.In recent years, abundant studies have reavling that LncRNAs are beneficial to the regulation of various cancer stem cells. Linc-ROR, as a newly discovered intergenic non-protein-coding RNA in recent years, is considered to be a key regulator affecting the development of human tumors. Dysregulation of Linc-ROR is related to stemness phenotype and functional regulation of cancer stem cells. For that, Linc-ROR has the potential to be used as a diagnostic biomarker for cancer patients and can serve as a clinically meaningful potential therapeutic target. In this review, we generalize the existing research results on the important role of Linc-ROR in regulation of CSCs.

Down-regulation of LINC-ROR, HOXA-AS2 and MEG3 in gastric cancer.

Long non-coding RNAs (lncRNAs) have been identified as modulators of gastric carcinogenesis. Evaluation of expression amounts of these transcripts is a primary but essential step for recognition of the role of lncRNAs in the carcinogenesis. Therefore, we compared expressions of LINC-ROR, HOXA-AS2, MEG3 and HOTTIP lncRNAs in gastric cancer samples and nearby non-cancerous samples. Expression levels of LINC-ROR, HOXA-AS2 and MEG3 lncRNAs have been lower in gastric cancer samples compared with nearby non-cancerous samples (Expression ratios = 0.26, 0.37 and 0.36; P values = 0.021, 0.015 and 0.032, respectively). However, expression levels of HOTTIP were not significantly different between gastric cancer tissues and nearby tissues (P value = 0.43). HOTTIP expression was associated with tumor size (P value = 0.04). In addition, MEG3 expression was associated with site of primary tumor (P = 0.0003). Expressions of LINC-ROR and HOXA-AS2 were not associated with any clinical or pathological parameter. ROC curve analysis revealed that HOXA-AS2 and LINC-ROR could significantly differentiate between gastric cancer samples and nearby non-cancerous tissues (AUC values = 0.68 and 0.64; P values = 0.01 and 0.04, respectively). Taken together, the current investigation provides clues for contribution of LINC-ROR, HOXA-AS2 and MEG3 lncRNAs in gastric carcinogenesis and warrants further mechanistical assays.

Differential Expression Pattern of linc-ROR Spliced Variants in Pluripotent and Non-Pluripotent Cell Lines.

OBJECTIVE: The human large intergenic non-coding RNA-regulator of reprogramming program (linc-ROR) is known as a stem cell specific linc-RNA. linc-ROR counteracts differentiation via sequestering microRNA-145 (miR-145) that targets OCT4 transcript. Despite the research on the expression and function, the exact structure of linc-ROR transcripts is not clear. Considering the contribution of alternative splicing in transcripts structures and function, identifying different spliced variants of linc-ROR is necessary for further functional analyses. We aimed to find the alternatively spliced transcripts of linc-ROR and investigate their expression pattern in stem and cancer cell lines and during neural differentiation of NT2 cells as a model for understanding linc-ROR role in stem cell and differentiation. MATERIALS AND METHODS: In this experimental study, linc-ROR locus was scanned for identifying novel exons. Different primer sets were used to detect new spliced variants by reverse transcription polymerase chain reaction (RT-PCR) and direct sequencing. Quantitative PCR (qPCR) and RT-PCR were employed to profile expression of linc-ROR transcripts in different cell lines and during neural differentiation of stem cells. RESULTS: We could discover 13 novel spliced variants of linc-ROR harboring unique array of exons. Our work uncovered six novel exons, some of which were the product of exonized transposable elements. Monitoring expression profile of the linc-ROR spliced variants in a panel of pluripotent and non-pluripotent cells exhibited that all transcripts were primarily expressed in pluripotent cells. Moreover, the examined linc-ROR spliced variants showed a similar downregulation during neural differentiation of NT2 cells. CONCLUSION: Altogether, our data showed despite the difference in the structure and composition of exons, various spliced variants of linc-ROR showed similar expression pattern in stem cells and through differentiation.

Tumor-derived exosomal lincRNA ROR promotes angiogenesis in nasopharyngeal carcinoma.

Long intergenic noncoding RNAs (lincRNAs) are expressed aberrantly in several malignancies, including nasopharyngeal carcinoma (NPC), where linc-ROR expression was found to be elevated. Being a hallmark of malignant tumors, angiogenesis has prompted us to investigate the impact of linc-ROR on NPC angiogenesis. This study demonstrates that linc-ROR is substantially expressed in serum exosomes from NPC and can be taken up by HUVECs. Using qRT-PCR, the CCK8 test, the transwell migration assay, the wound healing assay, and the tube formation assay, we demonstrated that linc-ROR increases proliferation, migration, and angiogenesis in vitro. Similar to prior research, our results have shown that linc-ROR can stimulate tumor angiogenesis in the zebrafish model. Thus, the p-AKT/p-VEGFR2 pathway is the mechanism by which linc-ROR affects the aforementioned biological activities. By stimulating angiogenesis, linc-ROR appears to play a significant role in the course of NPC and could account for a therapeutic target.

Role of Long Noncoding RNA Regulator of Reprogramming in Colon Cancer Progression via Epidermal Growth Factor Receptor Signaling.

Background: Long intergenic noncoding RNA regulator of reprogramming (linc-ROR) is a novel long noncoding RNA that exhibits significant effects on cancer progression. This research presented that linc-ROR had a crucial part in promoting biological characteristics associated with worse prognosis in colon cancer. Method: Bioinformatics analysis was performed to predict signaling pathways related to linc-ROR. In addition, western blot, quantitative reverse transcription-polymerase chain reaction, RNA-pulldown, cell proliferation assays, colony formation assays, wound healing assays, and transwell assays were applied to detect the role and regulation of particular molecules. Results: Our results showed that the knockdown of linc-ROR reduced cell invasion, proliferative ability, and migration in colon cancer. Further evaluation verified that downregulating linc-ROR inhibited the activation of epidermal growth factor receptor (EGFR) signaling. In addition, cbl-b, a kind of E3 ubiquitin ligase that increases the degradation of EGFR, was found to be a potential linc-ROR target. Conclusions: Based on our findings, it was presented that linc-ROR served a role as a tumor-promoting factor via repressing the ubiquitination and degradation of EGFR signaling, which indicated that it could be a possible prognostic marker and therapeutic target for colon cancer.

Functions of long non-coding RNA ROR in patient-derived glioblastoma cells.

Glioblastoma (GBM) is the most frequent and aggressive primary brain cancer in adult patients. A variety of long non-coding RNAs play an important role in the pathogenesis of GBM, however the molecular functions of most of them still remain elusive. Here, we investigated linc-RoR (long intergenic non-protein coding RNA, regulator of reprogramming) using GBM neurospheres obtained from 12 different patients. We demonstrated that the highest level of this transcript is detected in cells with increased EGFR expression. According to our data, linc-RoR knockdown decreases cell proliferation, increases sensitivity to DNA damage, and downregulates the level of cancer stem cell (CSC) markers. On the other hand, linc-RoR overexpression promote cell growth and increases the proportion of CSCs. Analysis of RNA sequencing data revealed that linc-RoR affects expression of genes involved in the regulation of mitosis. In agreement with this observation, we have showen that the highest level of linc-RoR is detected in the G2/M phase of the cell cycle, when linc-RoR is localized on the chromosomes of dividing cells. Based on our results, we can propose that linc-RoR performs pro-oncogenic functions in human gliobalstoma cells, which may be associated with the regulation of mitotic progression and GBM stemness.

Genotype Triad for HOTAIR rs10783618, LINC-ROR rs1942347, and MALAT1 rs3200401 as Molecular Markers in Systemic Lupus Erythematous.

Accumulating evidence supports the implication of long non-coding RNAs (lncRNAs) in autoimmune diseases, including systemic lupus erythematosus (SLE). LncRNA variants could impact the development and/or outcome of the disease with variable diagnostic/prognostic utility in the clinic. We aimed to explore the contribution of HOTAIR (rs10783618), LINC-ROR (rs1942347), and MALAT1 (rs3200401) variants to SLE susceptibility and/or severity in 163 SLE patients and age-/sex-matched controls using real-time TaqMan allelic discrimination PCR. HOTAIR rs10783618*C/C was associated with a 77% increased risk of SLE (OR = 1.77, 95%CI = 1.09−2.87, p = 0.020) under the recessive model. Similarly, MALAT1 rs3200401*T/T carriers were three times more likely to develop SLE (OR = 2.89, 95%CI = 1.42−5.90) under the recessive model. While the rs3200401*T/C genotype was associated with a 49−57% decreased risk of SLE under codominant (OR = 0.51, 95%CI = 0.31−0.82, p < 0.001) and over-dominant (OR = 0.43, 95%CI = 0.27−0.68, p < 0.001) models. LINC-ROR rs1942347*A/A patients were more likely to have a positive family history of SLE. At the same time, HOTAIR rs10783618*C/C was associated with a higher frequency of arthritis (p = 0.001) and the presence of oral ulcers (p = 0.002), while patients carrying rs10783618*T/T genotype were more likely to develop hair loss (p < 0.001), weight loss (p = 0.001), and neurological symptoms (p = 0.003). In conclusion, the studied lncRNAs, HOTAIR, and MALAT1 gene polymorphisms confer susceptibility for SLE, providing a potential theoretical basis for their clinical translation in SLE disease.

Prognostic Value of LINC-ROR (rs1942347) Variant in Patients with Colon Cancer Harboring BRAF Mutation: A Propensity Score-Matched Analysis.

Emerging studies show that long intergenic non-protein coding RNA, regulator of reprogramming (LINC-ROR) is aberrantly expressed in several types of cancer, including colon cancer (CC). LINC-ROR intronic variant rs1942347 may impact gene regulation and disease phenotype. We aimed to explore the potential association of LINC-ROR (rs1942347) with the clinicopathological features and outcome of CC cases. Archived FFPE (n = 180) CC samples were enrolled. Taq-Man allelic discrimination PCR was used for genotyping in propensity-matched cohorts with/without positive staining for mutant BRAF protein after eliminating confounders bias. The rs1942347*A allele variant was associated with high pathological grade, larger tumor size, distant metastasis, and mortality. Multiple logistic regression analysis adjusted by sex and BRAF mutation showed A/A genotype carriers to have 3 times more risk of early onset of cancer (OR = 3.13, 95%CI = 1.28-7.69, p = 0.034) than T/T genotype carriers. Overall analysis showed that rs1942347*A allele carriers had higher risk of mortality under heterozygote (OR = 2.13, 95%CI = 1.08-4.35, p = 0.003), homozygote (OR = 5.0, 95%CI = 1.69-14.29, p = 0.003), dominant (OR = 3.33, 95%CI = 1.20-9.09, p = 0.003), and recessive (OR = 2.63, 95%CI = 1.37-5.0, p = 0.011) models compared to T/T allele carriers. Stratified analysis by BRAF status revealed that the ancestor T/T allele conferred protection in BRAF mutant CC patients and was associated with a 73-93% reduced risk of mortality under heterozygote/homozygote comparison models. Using Kaplan-Meier curves, carriers of the A/A genotype had shorter survival times than T/T cohorts. The univariate Cox regression model revealed that the A/A genotype was associated with a 3.5 times greater mortality risk than the T/T genotype. However, after adjustment by multiple Cox regression analysis, the risk was insignificant. In conclusion, this is the first study identifying the potential association of the LINC-ROR (rs1942347) variant with CC prognosis.

Linc-ROR genetic variants are associated with the advanced disease in oral squamous cell carcinoma.

OBJECTIVE: The objective of this study is to identify the association between linc-ROR genetic variants and oral squamous cell carcinoma tumorigenesis. DESIGN: Four genetic variants of linc-ROR (rs6420545, rs4801078, rs1942348, and rs9636089) were analyzed in 178 OSCCs and 191 controls of the South Indian population by PCR amplification followed by restriction digestion. In addition, we examined whether these variants alter linc-ROR expression levels and the progression of OSCC. RESULTS: The frequency of linc-ROR rs6420545 and rs4801078 genotypes were significantly associated with advanced tumor grade (>2) (p = 0.002 and p = 0.048), and nodal metastasis (p = 0.001 and p = 0.019), respectively. We observed a significant association of rs6420545 specifically in the over-dominant model [OR 1.77 (95%CI; 1.17-2.68); p = 0.006] and rs9636089 in dominant model [OR 2.17 (95%CI; 1.06 - 4.46); p = 0.03], and allelic model [OR 2.26 (95%CI; 1.13 - 4.53) p = 0.02], respectively. Further, significant upregulation of linc-ROR (p = 0.005) was observed in our cohort, consistent with the HNSCC TCGA dataset (p < 0.0001). CONCLUSIONS: Our findings suggest that the linc-ROR genetic variants could contribute to the metastasis and progression mainly in the late event of tumorigenesis of OSCCs and these variants could be useful in the precision therapeutic management of this cancer particularly in prognosis.

Linc-ROR has a Potential ceRNA Activity for OCT4A by Sequestering miR-335-5p in the HEK293T Cell Line.

Linc-ROR has a regulatory role in reprogramming, and the core stem cell transcription factors, OCT4, SOX2, and NANOG, regulate its expression. MicroRNAs (miRNAs) are also a critical constituent of pivotal posttranscriptional regulatory pathways. One of such interactions is a competing endogenous RNA interaction that connects small and long non-coding RNAs with coding transcripts. Here, we aimed to investigate the existence of such associations between OCT4A, Linc-ROR, hsa-miR-335-5p, and hsa-miR-544. Bioinformatic analysis was performed to evaluate the expression status of OCT4A, Linc-ROR, miR-335, and miR-544 throughout differentiation as well as in various differentiated cells. The complete lengths of OCT4A and Linc-ROR, and OCT4A 3'-UTR were cloned in the luciferase reporter vector, and the precursors of miR-335 and miR-544 were cloned in expression vectors. Following the overexpression of miR-335 and miR-544 in the 5637 cell line, the endogenous expression of OCT4A and Linc-ROR was evaluated. Afterward, the expression vectors of miRNAs and the reporter vectors of OCT4A/Linc-ROR were co-transfected in the HEK293T cell line. Via the Dual-Luciferase assay, the effect of the overexpression of miRNAs on their two possible targets (Linc-ROR and OCT4A) was investigated. The bioinformatic analysis demonstrated a relatively similar expression pattern for OCT4A and Linc-ROR, while miR-335 showed a different expression status. Both miR-335 and miR-544 inhibited the endogenous expression of OCT4A. The Dual-Luciferase assay likewise confirmed the inhibitory effect of miR-335 and miR-544 on OCT4A expression. In contrast, the miR-335 inhibitory effect was reversed in the presence of Linc-ROR, resulting in the upregulation of OCT4A. Such evidence suggests that Linc-ROR may compete with OCT4A to interact with miR-335.