Cathepsins mediate tumor metastasis

Recently, super-enhancers (SEs) have been identified as a unique type of transcriptional regulation involved in cancer development. SEs exhibit a size, high transcription factor density, and strong binding to the transcriptional machinery compared with typical enhancers. SEs play an essential role in cell growth, differentiation, and disease initiation and progression including tumorigenesis. In particular, cancer-specific SEs have been proven to be key oncogenic drivers types of tumor cells. Furthermore, it has been confirmed that cancer-specific SEs can mediate the dysregulation of signaling pathways and promote cancer cell growth. Additionally, therapeutic strategies directly targeting SE components, for example, by disrupting SE structure or inhibiting SE cofactors, have shown a good curative effect on various cancers.

Super-enhancers (SEs) consist of a cluster of many enhancers bound to a great number of transcription factors. They are critical cis-regulatory elements that determine the identity of various human cell types. During tumorigenesis, DNA mutations and indels, chromosomal rearrangements, three-dimensional chromatin structural changes, and viral infections mediate oncogenic SE activation, and activated SEs have been found to regulate the expression of oncogenic genes. Inhibition specifically targeted to oncogenic SE assembly and activation provides a novel powerful therapeutic strategy for various cancers. In this paper, we first introduce the current understanding of oncogenic SE assembly and activation and then summarize the pathogenic factors and mechanism of oncogenic SE activation. Next, we elaborate on the oncogenic functions of SEs in cancers and the application of SEs as therapeutic targets. Finally, we turn our focus to the use of SEs in basic research and clinical trials.

Ezrin is highly expressed in metastatic tumors and is involved in filopodia formation as well as promotion of tumor metastasis. Thus, Ezrin may serve as a potential target for anti-metastatic therapy. This study demonstrates that berberine reduces filopodia formation of a nasopharyngeal carcinoma (NPC) cell line, 5-8F, at non-cytotoxic concentrations. Furthermore, invasion and motility of 5-8F cells are decreased in a dose- and time-dependent manner, resulting in 73.0% invasion and 67.0% motility inhibition at 20 μm. The inhibitory effects of berberine on 5-8F cell metastasis were further confirmed in a mouse model of metastasis. Berberine treatment in vivo resulted in a 51.1% inhibition of tumor metastasis to the lymph nodes and decreased Ezrin phosphorylation at threonine 567 in metastatic samples. Berberine suppressed the presence of phosphorylated Ezrin (phospho-Ezrin) in a dose- and time-dependent manner but had no effect on total Ezrin protein expression at non-cytotoxic concentrations. Furthermore, the inhibitory effects of berberine on phospho-Ezrin were dependent on the suppression of Rho kinase activity. Reduction of Ezrin phosphorylation at Thr⁵⁶⁷ by berberine was associated with its inhibitory effect on filopodia formation in 5-8F cells. However, berberine did not effectively inhibit the motility and invasion of NPC cells containing Ezrin Thr⁵⁶⁷ mutants. These results confirm that berberine inhibits Ezrin phosphorylation at Thr⁵⁶⁷. Nonetheless, berberine reduces motility and invasion of cells and inhibits tumor metastasis. The reduction of Rho kinase-mediated Ezrin phosphorylation mediated by berberine may be a novel anti-metastatic pathway in NPC 5-8F cells.

Nucleic acid aptamers are a class of high-affinity nucleic acid ligands. They serve as “chemical antibodies” since their high affinity and specificity. Nucleic acid aptamers are generated from nucleic acid random-sequence using a systematic evolution of ligands by exponential enrichment (SELEX) technology. SELEX is a process of effectively selecting aptamers from different targets. A newly developed cell-based SELEX technique has been widely used in biomarker discovery, early diagnosis and targeted cancer therapy, particular at colorectal cancer (CRC). Combined with nanostructures, nano-aptamer-drug delivery system was constructed for drug delivery. Various nanostructures functionalized with aptamers are highly efficient and has been used in CRC therapeutic applications. In the present, we introduce a cell- SELEX technique, and summarize the potential application of aptamers as biomarkers in CRC diagnosis and therapy. And some characteristics of aptamer-targeted nanocarriers in CRC have been expatiated. The challenges and perspectives for cell-SELEX are also discussed.

Although novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐mediated pulmonary inflammation has recently attracted great attention, its pathology and pathogenesis are not clear. Notably, due to both its high infective and pathogenicity, SARS‐CoV‐2 infection may cause a severe sometimes fatal respiratory disease. A specific vaccine, which relies on the analysis of SARS‐CoV‐2 structural protein‐derived antigenic peptides, is indispensable for restraining the spread and reducing the mortality of SARS‐CoV‐2. SARS‐CoV‐2 infections activate cytototxic, myeloid‐derived suppressor cells, dendritic cells, macrophages, as well as natural killer, B, helper T, and regulatory T cells, thus further stimulating innate and antigen‐specific immune responses. Nevertheless, many immune effector cells cause hyperinflammation and pulmonary immunopathology by releasing proinflammatory cytokines and chemokines, including interferon (IFN)‐α, IFN‐β, IFN‐γ, monocyte chemoattractant protein‐1, macrophage inflammatory protein (MIP)‐1A, MIP1B, interleukin (IL)‐1, IL‐2, IL‐4, IL‐6, IL‐7, IL‐8, IL‐9, IL‐12, IL‐17, and IL‐18, platelet‐derived growth factor, fibroblast growth factor, tumor necrosis factor‐α, and induced protein 10. Interestingly, related products derived from SARS‐CoV‐2 are likely to trigger immune evasion. Therefore, investigating SARS‐CoV‐2‐specific vaccines, blocking immunopathology, and prohibiting immune evasion are urgently required for treating SARS‐CoV‐2 infection. In this review, we emphatically illuminated the development of a SARS‐CoV‐2‐specific vaccine based on the analysis of epitopes, also expounding the molecular mechanisms of SARS‐CoV‐2‐mediated cytokine release syndrome. Furthermore, we comprehensively discussed SARS‐CoV‐2‐associated immune evasion and lung immunopathology. Lastly, potential therapeutic strategies against SARS‐CoV‐2 were explored.