LncmiRHG-MIR100HG: A new budding star in cancer.

MIR100HG, also known as lncRNA mir-100-let-7a-2-mir-125b-1 cluster host gene, is a new and critical regulator in cancers in recent years. MIR100HG is dysregulated in various cancers and plays an oncogenic or tumor-suppressive role, which participates in many tumor cell biology processes and cancer-related pathways. The errant expression of MIR100HG has inspired people to investigate the function of MIR100HG and its diagnostic and therapeutic potential in cancers. Many studies have indicated that dysregulated expression of MIR100HG is markedly correlated with poor prognosis and clinicopathological features. In this review, we will highlight the characteristics and introduce the role of MIR100HG in different cancers, and summarize the molecular mechanism, pathways, chemoresistance, and current research progress of MIR100HG in cancers. Furthermore, some open questions in this rapidly advancing field are proposed. These updates clarify our understanding of MIR100HG in cancers, which may pave the way for the application of MIR100HG-targeting approaches in future cancer diagnosis, prognosis, and therapy.

Correction: Li et al. Identification and Characterization of Cancer Stem-Like Cells in ALK-Positive Anaplastic Large Cell Lymphoma Using the SORE6 Reporter. Curr. Issues Mol. Biol. 2021, 43, 543-557.

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Delivery of DNA octahedra enhanced by focused ultrasound with microbubbles for glioma therapy.

DNA nanostructures, with good biosafety, highly programmable assembly, flexible modification, and precise control, are tailored as drug carriers to deliver therapeutic agents for cancer therapy. However, they face considerable challenges regarding their delivery into the brain, mainly due to the blood-brain barrier (BBB). By controlling the acoustic parameters, focused ultrasound combined with microbubbles (FUS/MB) can temporarily, noninvasively, and reproducibly open the BBB in a localized region. We investigated the delivery outcome of pH-responsive DNA octahedra loading Epirubicin (Epr@DNA-Octa) via FUS/MB and its therapeutic efficiency in a mouse model bearing intracranial glioma xenograft. Using FUS/MB to locally disrupt the BBB or the blood-tumor barrier (BTB) and systemic administration of Epr@DNA-Octa (Epr@DNA-Octa + FUS/MB) (2 mg/kg of loaded Epr), we achieved an Epr concentration of 292.3 ± 10.1 ng/g tissue in glioma, a 4.4-fold increase compared to unsonicated animals (p < 0.001). The in vitro findings indicated that Epr released from DNA strands accumulated in lysosomes and induced enhanced cytotoxicity compared to free Epr. Further two-photon intravital imaging of spatiotemporal patterns of the DNA-Octa leakage revealed that the FUS/MB treatment enhanced DNA-Octa delivery across several physiological barriers at microscopic level, including the first extravasation across the BBB/BTB and then deep penetration into the glioma center and engulfment of DNA-Octa into the tumor cell body. Longitudinal in vivo bioluminescence imaging and histological analysis indicated that the intracranial glioma progression in nude mice treated with Epr@DNA-Octa + FUS/MB was effectively retarded compared to other groups. The beneficial effect on survival was most significant in the Epr@DNA-Octa + FUS/MB group, with a 50% increase in median survival and a 73% increase in the maximum survival compared to control animals. Our work demonstrates the potential viability of FUS/MB as an alternative strategy for glioma delivery of anticancer drugs using DNA nanostructures as the drug delivery platform for brain cancer therapy.

Expression and prognostic analysis of BGN in head and neck squamous cell carcinoma.

OBJECTIVE: BGN belongs to class of small leucine rich proteoglycans, which is high expression in plenty of human cancers. However, the detailed role of BGN remains unclear in Head and neck squamous cell carcinoma (HNSC). MATERIALS AND METHODS: In this study, we assessed the transcriptional expression, protein expression, prognosis, co-expressed genes, functional enrichment, and hub genes in HNSC patients based on the data published in the following databases: ONCOMINE, GEPIA, GEO, LinkedOmics, and HPA databases. Data from the TCGA database was used to analyze the correlations between BGN expression and different clinicopathological features, as well as prognostic analysis. RESULTS: We found that the expression of BGN is higher in patients with HNSC than in control tissues. Pathologically, high BGN expression was significantly correlated with T3 and T4 stage. Besides, high expression of BGN is a poor prognostic factor for overall surviva, not disease free survival. The co-expression genes associated with BGN expression exhibited enriched in various function and pathway, such as extracellular matrix, mitochondrion, PI3K-Akt signaling pathway. A total of 10 hub genes were identified from the co-expressed genes, within which five genes, including FSTL1, LAMB1, SDC2, VCAN, and IGFBP7, were significantly increased in patient's with HNSC. BGN exhibited weak correlations with tumor-infiltrating CD4+ T, macrophages cell, and dendritic cells. Futhermore, many markers of infiltrating immune cells, such as Treg, showed different BGN-related immune infiltration patterns. BGN expression showed strong correlations with diverse immune marker sets in COAD and STAD. CONCLUSIONS: Our results demonstrated that BGN is high expression in HNSC and is a poor prognostic factor for clinical outcome in patients with HNSC. It could serve as a potential prognostic biomarker for patients survival in HNSC.

Identification of biomarkers for acute leukemia via machine learning-based stemness index.

Traditional methods to understand leukemia stem cell (LSC)'s biological characteristics include constructing LSC-like cells and mouse models by transgenic or knock-in methods. However, there are some potential pitfalls in using this method, such as retroviral insertion mutagenesis, non-physiological level gene expression, non-physiological expansion, and difficulty to construct. The mRNAsi index for each sample of the Cancer Genome Atlas (TCGA) could avoid these potential pitfalls by machine learning. In this work, we aimed to construct a network of LSC genes utilizing the mRNAsi. First, mRNAsi value was analyzed with expressions distributions, survival analysis, age, and gender in acute myeloid leukemia (AML) samples. Then, we used the weighted gene co-expression network analysis (WGCNA) to construct modules of stemness genes. The correlation of the LSC genes transcription and interplay among LSC proteins was analyzed. We performed functional and pathway enrichment analysis to annotate stemness genes. Survival analysis further identified prognostic biomarkers by clinical data of TCGA and the Gene Expression Omnibus (GEO) database. We found that the result of mRNAsi overall survival is not significant, which may be due to the heterogeneity of AML in the stage of myeloid differentiation, French-American-British (FAB) classification systems. Enrichment analysis indicated that the stemness genes were biologically clustered as a group and mainly associated with cell cycle and mitosis. Moreover, 10 key genes (SNRNP40, RFC4, RFC5, CDC6, HSPE1, PA2G4, SNAP23P, DARS2, MIS18A, and HPRT1) were screened by survival analysis with the data from TCGA and GEO. Among them, RFC4 and RFC5 were the distinguished biomarkers for their double-validated prognostic value in both databases. Additionally, the expression of RFC4 and RFC5 had the same trend as mRNAsi score in FAB subtypes. In conclusion, our result demonstrated that mRNAsi based LSC-related genes were found to have strong interactions as a cluster. These genes, especially RFC4 and RFC5, could be the therapeutic targets for inhibiting the stemness characteristics of AML. This work is also a comprehensive pipeline for future cancer stem cell studies.

Identification and Characterization of Cancer Stem-Like Cells in ALK-Positive Anaplastic Large Cell Lymphoma Using the SORE6 Reporter.

Transcription factors Sox2 and Oct4 are essential in maintaining the pluripotency of embryonic stem cells and conferring stemness in cancer stem-like (CSL) cells. SORE6, an in-vitro reporter system, was designed to quantify the transcription activity of Sox2/Oct4 and identify CSL cells in non-hematologic cancers. Using SORE6, we identified and enriched CSL cells in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). Two ALK + ALCL cell lines, SupM2 and UCONN-L2, contained approximately 20% of SORE6+ cells, which were purified based on their expression of green fluorescent protein. We then performed functional studies using single-cell clones derived from SORE6- and SORE6+ cells. Compared to SORE6- cells, SORE6+ cells were significantly more chemoresistant and clonogenic in colony-formation assays. Sox2/Oct4 are directly involved in conferring these CSL properties, since the shRNA knockdown of Sox2 in SORE6+ significantly lowered their chemoresistance, while enforced expression of Sox2/Oct4 in SORE6- cells produced opposite effects. Using Western blots, we found that the expression and subcellular localization of Sox2/Oct4 were similar between SORE6- and SORE6+ cells. However, in SORE6+ but not SORE6- cells, Sox2 and Oct4 abundantly bound to a probe containing the SORE6 consensus sequence. c-Myc, previously shown to regulate cancer stemness in ALK + ALCL, regulated the SORE6 activity. In conclusion, SORE6 is useful in identifying/enriching CSL cells in ALK + ALCL.

Crizotinib Resistance Mediated by Autophagy Is Higher in the Stem-Like Cell Subset in ALK-Positive Anaplastic Large Cell Lymphoma, and This Effect Is MYC-Dependent.

Previously it was shown that autophagy contributes to crizotinib resistance in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We asked if autophagy is equally important in two distinct subsets of ALK + ALCL, namely Reporter Unresponsive (RU) and Reporter Responsive (RR), of which RR cells display stem-like properties. Autophagic flux was assessed with a fluorescence tagged LC3 reporter and immunoblots to detect endogenous LC3 alongside chloroquine, an autophagy inhibitor. The stem-like RR cells displayed significantly higher autophagic response upon crizotinib treatment. Their exaggerated autophagic response is cytoprotective against crizotinib, as inhibition of autophagy using chloroquine or shRNA against BECN1 or ATG7 led to a decrease in their viability. In contrast, autophagy inhibition in RU resulted in minimal changes. Since the differential protein expression of MYC is a regulator of the RU/RR dichotomy and is higher in RR cells, we asked if MYC regulates the autophagy-mediated cytoprotective effect. Inhibition of MYC in RR cells using shRNA significantly blunted crizotinib-induced autophagic response and effectively suppressed this cytoprotective effect. In conclusion, stem-like RR cells respond with rapid and intense autophagic flux which manifests with crizotinib resistance. For the first time, we have highlighted the direct role of MYC in regulating autophagy and its associated chemoresistance phenotype in ALK + ALCL stem-like cells.

Prognostic significance of glutathione peroxidase 2 in gastric carcinoma.

Increasing evidence suggests that the glutathione peroxidase 2 may actually play important roles in tumorigenesis and progression in various human cancers such as colorectal carcinomas and lung adenocarcinomas. However, the role of glutathione peroxidase 2 in gastric carcinoma remains to be determined. In this study, the expression and prognostic significance of glutathione peroxidase 2 in gastric carcinoma were investigated and the well-known prognostic factor Ki-67 labeling index was also assessed as positive control. Glutathione peroxidase 2 expression levels in the tumor tissue specimens, the matched adjacent normal tissue specimens, and the lymph node metastases of 176 patients with gastric carcinoma were evaluated by quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The associations between glutathione peroxidase 2 expression levels, as determined by immunohistochemical staining, and multiple clinicopathological characteristics were determined by Pearson's chi-square test and Spearman's correlation analysis. The relationships between glutathione peroxidase 2 expression and other clinicopathological variables and patient prognoses were analyzed further by the Kaplan-Meier method, the log-rank test, and Cox multivariate regression. The quantitative polymerase chain reaction, western blotting, and immunohistochemical staining results showed that glutathione peroxidase 2 expression levels were upregulated in both the primary tumor foci and the lymph node metastases of patients with gastric carcinoma (all p values < 0.05). Furthermore, Pearson's chi-square tests, as well as Spearman's correlation analysis, revealed that glutathione peroxidase 2 expression levels were strongly correlated with the Ki-67 labeling index, differentiation, histological patterns, Lauren classifications, lymph node metastasis, vascular invasion, tumor-node-metastasis stages, Helicobacter pylori infection, and overall survival (all p values < 0.05). Kaplan-Meier analysis, as well as the log-rank test and multivariate Cox regression analysis, showed that multiple clinicopathological risk factors and glutathione peroxidase 2 expression were novel independent prognostic factors for gastric carcinoma (all p values < 0.05). Glutathione peroxidase 2 expression is a novel independent prognostic biomarker for gastric carcinoma that may be used to devise personalized therapeutic regimens and precision treatments for this disease.

In vitro differentiation of endometrial regenerative cells into smooth muscle cells: Α potential approach for the management of pelvic organ prolapse.

Pelvic organ prolapse (POP), is a common condition in parous women. Synthetic mesh was once considered to be the standard of care; however, the use of synthetic mesh is limited by severe complications, thus creating a need for novel approaches. The application of cell-based therapy with stem cells may be an ideal alternative, and specifically for vaginal prolapse. Abnormalities in vaginal smooth muscle (SM) play a role in the pathogenesis of POP, indicating that smooth muscle cells (SMCs) may be a potential therapeutic target. Endometrial regenerative cells (ERCs) are an easily accessible, readily available source of adult stem cells. In the present study, ERCs were obtained from human menstrual blood, and phase contrast microscopy and flow cytometry were performed to characterize the morphology and phenotype of the ERCs. SMC differentiation was induced by a transforming growth factor ß1-based medium, and the induction conditions were optimized. We defined the SMC characteristics of the induced cells with regard to morphology and marker expression using transmission electron microscopy, western blot analysis, immunocytofluorescence and RT-PCR. Examining the expression of the components of the Smad pathway and phosphorylated Smad2 and Smad3 by western blot analysis, RT-PCR and quantitative PCR demonstrated that the 'TGFBR2/ALK5/Smad2 and Smad3' pathway is involved, and both Smad2 and Smad3 participated in SMC differentiation. Taken together, these findings indicate that ERCs may be a promising cell source for cellular therapy aimed at modulating SM function in the vagina wall and pelvic floor in order to treat POP.

S-1 combined with cisplatin versus cisplatin alone for the treatment of advanced gastric cancer: a pilot randomized-controlled trial.

We aimed to assess the efficacy and safety of S-1 combined with cisplatin (SC) over cisplatin alone (C) for the treatment of advanced gastric cancer in China. Between July 2009 and June 2011, 72 eligible patients with advanced gastric cancer were selected and divided randomly into two groups. Thirty-six patients received SC, with S-1 on days 1 through 14 of a 21-day cycle and cisplatin (60 mg/m on day 1) every 4 weeks for two cycles. The other 36 patients were administered only cisplatin (in the same manner as SC). The primary outcome was overall survival. The secondary outcomes were progression-free survival and adverse events. The 2-year overall response rate was 51.5 and 42.3% for the SC and C groups, respectively, and the difference was statistically significant, whereas the median overall survival was 9.4 months (range, 1.9-24.4 months) and 7.6 months (range, 1.7-21.4 months), respectively (P=0.039). The median progression-free survival was 7.7 months for SC (range, 1.8-19.4 months), whereas it was 6.5 months (range, 1.5-16.4 months) for C (P=0.047). The toxicity profile was similar in both groups. In summary, we have shown that S-1 combined with cisplatin is more effective, with acceptable toxicity in comparison with cisplatin alone in Chinese patients with advanced gastric cancer. Chinese Clinical Trials Register: ChiCTR-TRC-13003993.