LncRNAs are involved in the initiation and progression of cancer. However, the molecular mechanism and diverse clinical prognosis of MIR31HG in head and neck squamous cell carcinoma (HNSCC) are still ...unclear. Our previous microarray analysis showed that lncRNA MIR31HG interacted with HIF1A may play an oncogenic role in laryngeal squamous cell cancer (LSCC). To determine whether lncRNA MIR31HG served as a poor prognosis factor and targeted HIF1A to facilitate cell proliferation and tumorigenesis in human HNSCC, we found MIR31HG and HIF1A were overexpressed in LSCC, MIR31HG overexpression or co-expression of HIF1A-positive and p21-negative could serve as a poor prognostic factor for LSCC patients. We further confirmed that MIR31HG promoted cell proliferation, cell cycle progression, and inhibited cell apoptosis in vitro and in vivo. The ingenuity pathway analysis and Western blot indicated that MIR31HG regulated cell cycle progression via HIF1A and p21 in HNSCC. The current results provide evidences for the role of MIR31HG in promoting HNSCC progression and identify MIR31HG as a prognostic biomarker and putative therapeutic target in HNSCC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing ...conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B-mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2-CCR2 signaling or cathepsin B function significantly impaired PNI
Correlative studies in human specimens demonstrated that cathepsin B-producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI.
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MiR-381-3p and nuclear autoantigenic sperm protein (NASP) have regulatory functions in tumors. Whether NASP is targeted by miR-381-3p to influence biological characteristics of cancer in head-neck ...squamous cell carcinoma (HNSCC) cells was investigated. StarBase (version 3.0) found that the expression of NASP was increased with the down-regulation of miR-381-3p in laryngocarcinoma tissue, AMC-HN-3，FaDu，HNE-3，and Detroit 562 cell lines. MiR-381-3p could target NASP, reduce the expression of MMP-2 and MMP-9, Vimentin, repress the cell viability, invasion, and migration, and promote the expression of E-cadherin in AMC-HN-3 cells. Overexpressed NASP could increase the viability, migration and invasion rates in AMC-HN-3 cells, which could be partially reversed by overexpressed miR-381-3p. Thus, miR-381-3p targeted and suppressed NASP gene, reduced the viability, migration, invasion, EMT of HNSCC cells, demonstrating that miR-381-3p has the potential to be a therapeutic target in inhibiting the progression of HNSCC.
Overexpression of miR-381-3p reversed the promotive effect of NASP on the viability, migration, and invasion of AMC-HN-3 cells.
The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial ...cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRα1 ⁺/⁻ mice compared with GFRα1 ⁺/⁺ mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRα1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRα1 expression, suggesting an alternate source of GFRα1 in PNI. These findings collectively demonstrate that GFRα1 released by nerves enhances PNI through GDNF-RET signaling and that GFRα1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Head and neck squamous cell carcinoma are one of the most common types of cancer worldwide. Although a variety of treatment methods such as surgery, radiotherapy, chemotherapy, and targeted therapy ...are widely used in diagnosing and treating HNSCC, the survival prognosis of patients has not been significantly improved in the past decades. As an emerging treatment approach, immunotherapy has shown exciting therapeutic effects in R/M HNSCC. However, the current screening methods are still insufficient, and there is a significant need for reliable predictive biomarkers for personalized clinical management and new therapeutic strategies. This review summarized the application of immunotherapy in HNSCC, comprehensively analyzed the existing bioinformatic studies on immunotherapy in HNSCC, evaluated the current methods of tumor immune heterogeneity and immunotherapy, and aimed to screen molecular markers with potential predictive significance. Among them, PD-1 has obvious predictive relevance as the target of existing immune drugs. Clonal TMB is a potential biomarker for HNSCC immunotherapy. The other molecules, including IFN-γ, CXCL, CTLA-4, MTAP, SFR4/CPXM1/COL5A1, TILs, CAFs, exosomes, and peripheral blood indicators, may have suggestive significance for tumor immune microenvironment and prognosis of immunotherapy.
Several recent studies have indicated that the lymph node ratio (LNR) is an independent prognostic factor for laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC). The purpose of this paper ...is to assess the prognostic value of LNR and explore appropriate cutoff values by conducting a systematic review and meta-analysis.
Pubmed, Embase (via Ovid), and Cochrane library were systematically searched for studies on the prognostic value of LNR in LHSCC up to October 31, 2019. Then, Literature review, data extraction, and quality assessment of eligible studies were performed by two independent reviewers back-to-back. Lastly, Stata 14.0 software was hired to conduct a meta-analysis.
A total of 445 articles were retrieved, and 13 studies published in English between 2013 and 2019 were included after the title/abstract and full-text screening. Among the 13 studies contributed to 4197 patients, seven studies were about hypopharyngeal squamous cell carcinoma (HPSCC), four studies about laryngeal squamous cell carcinoma (LSCC), and the remaining two studies about LHSCC. The meta-analysis results showed that shorter overall survival (OS) (HR 1.49; 95%CI: 1.18 to 1.88), disease-specific survival (DSS) (HR 1.66; 95%CI: 1.32 to 2.07) and disease-free survival (DFS) (HR 2.04; 95%CI: 1.54 to 2.71) were significantly correlated with a higher LNR in a random-effect model. The cutoff values of eligible studies were varied from 0.03 to 0.14, and the lowest significant LNR was 0.044.
LNR is a valuable prognostic factor in the survival of LHSCC and may be used to improve the tumor staging systems, which, however, requires the solid support of more high-quality studies.
Perineural invasion (PNI) is an ominous form of cancer progression along nerves associated with poor clinical outcome. Glial derived neurotrophic factor (GDNF) interacts with cancer cell RET ...receptors to enable PNI, but downstream events remain undefined. We demonstrate that GDNF leads to early activation of the GTPase Cdc42 in pancreatic cancer cells, but only delayed activation of RhoA and does not affect Rac1. Depletion of Cdc42 impairs pancreatic cancer cell chemotaxis toward GDNF and nerves. An siRNA library of guanine nucleotide exchange factors was screened to identify activators of Cdc42. ARHGEF7 (β-Pix) was required for Cdc42 activation and chemotaxis toward nerves, and also colocalizes with RET under GDNF stimulation. Cdc42 enables PNI in an
dorsal root ganglia coculture model, and controls the directionality of migration but does not affect cell speed or cell viability. In contrast, Rac1 was necessary for cell speed but not directionality, while the RhoA was not necessary for either cell speed or directionality. Cdc42 was required for PNI in an
murine sciatic nerve model. Depletion of Cdc42 significantly diminished the length of PNI, volume of PNI, and motor nerve paralysis resulting from PNI. Activated Cdc42 is expressed in human salivary ductal cancer cells invading nerves. These findings establish the GDNF-RET-β-Pix-Cdc42 pathway as a directional regulator of pancreatic cancer cell migration toward nerves, highlight the importance of directional migration in PNI, and offer novel targets for therapy. IMPLICATIONS: Cdc42 regulates cancer cell directional migration toward and along nerves in PNI.
Long non-coding RNA (lncRNA) is involved in the progression of head and neck squamous cell carcinoma (HNSCC). The molecular mechanism of lncRNA SOX2-OT in HNSCC remains unclear. Therefore, we aimed ...to elucidate the oncogenic role of SOX2-OT in HNSCC. QRT-PCR analysis was performed in 61 pairs of HNSCC cancer tissues, adjacent normal tissues, and 68 plasma samples confirmed that lncRNA SOX2-OT was overexpressed in cancer tissues and plasma samples, which served as a poor prognostic factor for HNSCC. The FISH assay demonstrated that SOX2-OT was localized in the nucleus and cytoplasm of HNSCC cell lines. Further, the cell function assay confirmed that SOX2-OT promoted cell proliferation and metastasis in vitro and in vivo. RNA pulldown and RIP assay results revealed that SOX2-OT bonds with ILF3 in HNSCC, and the rescue assay confirmed that SOX2-OT played an oncogenic role depending on ILF3 protein expression. Ingenuity pathway analysis and Western blotting indicated that SOX2-OT regulated HNSCC progression by promoting STAT3 phosphorylation and modulating the crosstalk between STAT3 and TGF-β signaling. These results reveal evidence for the role of SOX2-OT in HNSCC progression and metastasis by binding to ILF3, which may serve as a therapeutic target and prognostic biomarker in HNSCC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Alongside China’s new round of electricity reform, Yunnan has implemented medium- and long-term market reform in the electricity sector since 2015 with little progress seen in establishing an ...electricity spot market. To this end, this paper attempts to identify the pathway to an electricity spot market for Yunnan through its realities and lessons learned from Europe. As such, on the ground of the status quo of the energy mix, generation features, load structure and profiles, power supply–demand situations, and market progress in the Yunnan electricity system, this paper reviews two classical market frameworks commonly adopted worldwide, from the perspectives of market organizing and the core optimization model broadly used in coordinating system operation and clearing the market. Then the contrast of Yunnan with the European experience is analyzed with respect to the energy mix, generation, transmission, and exchange, as well as the political and economic institutional arrangements, market conditions, and driving forces. Moreover, the Yunnan case study scenarios and likely consequences and benefits under different market frameworks are further analyzed to verify the edge of a centralized optimal-power-flow-based regional market over a decentralized cross-province balancing market, in productively reducing price distortion, allocating resources, maintaining power supply–demand balance at all times, and promoting renewable energy integration across a wider region. Finally, policy suggestions concerning the pathway to an electricity spot market are provided for Yunnan in further deepening its electricity reform.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Perineural invasion is a form of cancer progression where cancer cells invade along nerves. This behavior is associated with poor clinical outcomes; therefore, it is critical to identify novel ...ligand-receptor interactions between nerves and cancer cells that support the process of perineural invasion. A proteomic profiler chemokine array was used to screen for nerve-derived factors secreted from tissue explants of dorsal root ganglion (DRG), and CCL2 was identified as a lead candidate. Prostate cancer cell line expression of CCR2, the receptor to CCL2, correlated closely with MAPK and Akt pathway activity and cell migration towards CCL2 and DRG. In vitro nerve and cancer coculture invasion assays of perineural invasion demonstrated that cancer cell CCR2 expression facilitates perineural invasion. Perineural invasion is significantly diminished in coculture assays when using DRG harvested from CCL2(-/-) knockout mice as compared with control CCL2(+/+) mice, indicating that CCR2 is required for perineural invasion in this murine model of perineural invasion. Furthermore, 20 of 21 (95%) patient specimens of prostate adenocarcinoma with perineural invasion exhibited CCR2 expression by immunohistochemistry, while just 3 of 13 (23%) lacking perineural invasion expressed CCR2. In summary, nerve-released CCL2 supports prostate cancer migration and perineural invasion though CCR2-mediated signaling.
These results reveal CCL2-CCR2 signaling as a key ligand-receptor mechanism that mediates cancer cell communication with nerves during perineural invasion and highlight a potential future therapeutic target.
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