Claudins are major integral membrane proteins of tight junctions. Altered expression of several claudin proteins, in particular claudin-1, -3, -4 and -7, has been linked to the development of various ...cancers. Although their dysregulation in cancer suggests that claudins play a role in tumorigenesis, the exact underlying mechanism remains unclear. The involvement of claudins in tumor progression was suggested by their important role in the migration, invasion and metastasis of cancer cells in a tissue-dependent manner. Recent studies have shown that they play a role in epithelial to mesenchymal transition (EMT), the formation of cancer stem cells or tumor-initiating cells (CSCs/TICs), and chemoresistance, suggesting that claudins are promising targets for the treatment of chemoresistant and recurrent tumors. A recently identified claudin-low breast cancer subtype that is characterized by the enrichment of EMT and stem cell-like features is significantly associated with disease recurrence, underscoring the importance of claudins as predictors of tumor recurrence. The critical role of epigenetic mechanisms in the regulation of claudin expression indicates the possible application of epigenetic therapy to target claudins. A better understanding of the emerging role of claudins in CSC/TICs and chemoresistance may help to develop therapies against recurrent cancers.
Matrix metalloproteinases (MMPs) are the most prominent proteinases involved in tumorigenesis. They were initially recognized to promote tumor progression by remodeling the extracellular matrix ...through their proteolytic activity. However, accumulating evidence has revealed that some MMPs have protective roles in cancer progression, and the same MMP can exert opposing roles depending on the cell type in which it is expressed or the stage of cancer. Moreover, studies have shown that MMPs are involved in cancer progression through their roles in other biological processes such as cell signaling and immune regulation, independent of their catalytic activity. Despite the prognostic significance of tumoral or stromal expression of MMPs in breast cancer, their roles and molecular mechanisms in breast cancer progression remain unclear. As the failures of early clinical trials with broad-spectrum MMP inhibitors were mainly due to a lack of drug specificity, substantial efforts have been made to develop highly selective MMP inhibitors. Some recently developed MMP inhibitory monoclonal antibodies demonstrated promising anti-tumor effects in preclinical models of breast cancer. Importantly, anti-tumor effects of these antibodies were associated with the modulation of tumor immune microenvironment, suggesting that the use of MMP inhibitors in combination with immunotherapy can improve the efficacy of immunotherapy in HER2-positive or triple-negative breast cancer. In this review, the current understanding of the roles of tumoral or stromal MMPs in breast cancer is summarized, and recent advances in the development of highly selective MMP inhibitors are discussed.
Several multigene assays have been developed to predict the risk of distant recurrence and response to adjuvant therapy in early breast cancer. However, the prognostic or predictive value of current ...proliferation gene signature-based assays are limited to hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) early breast cancer. Considerable discordance between the different assays in classifying patients into risk groups has also been reported, thus raising questions about the clinical utility of these assays for individual patients. Therefore, there still remains a need for better prognostic or predictive biomarkers for breast cancer. The role of immune cells comprising tumor microenvironment in tumor progression has been recognized. Accumulating evidences have shown that immune gene signatures and tumor-infiltrating lymphocytes (TILs) can be prognostic or predictive factors in breast cancer, particularly with regard to HER2+ and triple-negative breast cancer. In this review, I summarize current multigene assays for breast cancer and discuss recent progress in identifying novel breast cancer biomarkers, focusing on the emerging importance of immune gene signatures and TILs as prognostic or predictive biomarkers.
As aberrant alternative splicing by either dysregulation or mutations of splicing factors contributes to cancer initiation and progression, splicing factors are emerging as potential therapeutic ...targets for cancer therapy. Therefore, pharmacological modulators targeting splicing factors have been under development. Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific splicing factor, whose downregulation is associated with epithelial-mesenchymal transition (EMT) by regulating alternative splicing of multiple genes, such as CD44, CTNND1, ENAH, and FGFR2. Consistent with the downregulation of ESRP1 during EMT, it has been initially revealed that high ESRP1 expression is associated with favorable prognosis and ESRP1 plays a tumor-suppressive role in cancer progression. However, ESRP1 has been found to promote cancer progression in some cancers, such as breast and ovarian cancers, indicating that it plays a dual role in cancer progression depending on the type of cancer. Furthermore, recent studies have reported that ESRP1 affects tumor growth by regulating the metabolism of tumor cells or immune cell infiltration in the tumor microenvironment, suggesting the novel roles of ESRP1 in addition to EMT. ESRP1 expression was also associated with response to anticancer drugs. This review describes current understanding of the roles and mechanisms of ESRP1 in cancer progression, and further discusses the emerging novel roles of ESRP1 in cancer and recent attempts to target splicing factors for cancer therapy.
RNase III Drosha initiates microRNA (miRNA) maturation by cleaving a primary miRNA transcript and releasing a pre-miRNA with a 2 nt 3′ overhang. Dicer recognizes the 2 nt 3′ overhang structure to ...selectively process pre-miRNAs. Here, we find that, unlike prototypic pre-miRNAs (group I), group II pre-miRNAs acquire a shorter (1 nt) 3′ overhang from Drosha processing and therefore require a 3′-end mono-uridylation for Dicer processing. The majority of let-7 and miR-105 belong to group II. We identify TUT7/ZCCHC6, TUT4/ZCCHC11, and TUT2/PAPD4/GLD2 as the terminal uridylyl transferases responsible for pre-miRNA mono-uridylation. The TUTs act specifically on dsRNAs with a 1 nt 3′ overhang, thereby creating a 2 nt 3′ overhang. Depletion of TUTs reduces let-7 levels and disrupts let-7 function. Although the let-7 suppressor, Lin28, induces inhibitory oligo-uridylation in embryonic stem cells, mono-uridylation occurs in somatic cells lacking Lin28 to promote let-7 biogenesis. Our study reveals functional duality of uridylation and introduces TUT7/4/2 as components of the miRNA biogenesis pathway.
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▸ Unlike canonical group I miRNA precursors, group II members have a 1 nt 3′ overhang ▸ Mono-uridylation of group II pre-let-7 promotes Dicer processing ▸ TUT7, TUT4, and TUT2 catalyze pre-let-7 mono-uridylation in cells lacking Lin28 ▸ Lin28 induces oligo-uridylation to inhibit let-7 processing
Group II precursors require mono-uridylation by TUTases to create the overhang of 2 nt required for Dicer processing. In the presence of Lin28, let-7 is preferably oligo-uridylated by TUT4 promoting its degradation, revealing the functional duality of uridylation.
Tomato is a widely distributed, cultivated, and commercialized vegetable crop. It contains antioxidant constituents including lycopene, tocopherols, vitamin C,
-aminobutyric acid, phenols, and ...flavonoids. This study determined the contents of the antioxidant components and activities of the pulp with skin of ten regular, six medium-sized, and two small cherry tomato cultivars at red ripe (BR + 10) stage cultivated in Korea. The relationships among the Hunter color coordinates, the content of each component, and antioxidant activities were measured by Pearson's correlation coefficients. As the
value increased, the carotenoid and vitamin C contents increased, while the
* value, hue angle and tocopherol content decreased. As the
value increased, the lycopene and total carotenoid contents decreased, and the flavonoid content in the hydrophilic extracts increased. The contents of vitamin C and total carotenoids including lycopene showed high positive correlations with the DPPH radical scavenging activities of both the lipophilic and hydrophilic extracts. Tocopherols and total phenolics in the hydrophilic and lipophilic extracts were not major positive contributors to the antioxidant activity. These findings suggest the quality standards for consumer requirements and inputs for on-going research for the development of better breeds.
Sound vibration (SV) is considered as an external mechanical force that modulates plant growth and development like other mechanical stimuli (e.g., wind, rain, touch and vibration). A number of ...previous and recent studies reported developmental responses in plants tailored against SV of varied frequencies. This strongly suggests the existence of sophisticated molecular mechanisms for SV perception and signal transduction. Despite this there exists a huge gap in our understanding regarding the SV-mediated molecular alterations, which is a prerequisite to gain insight into SV-mediated plant development. Herein, we investigated the global gene expression changes in Arabidopsis thaliana upon treatment with five different single frequencies of SV at constant amplitude for 1 h. As a next step, we also studied the SV-mediated proteomic changes in Arabidopsis. Data suggested that like other stimuli, SV also activated signature cellular events, for example, scavenging of reactive oxygen species (ROS), alteration of primary metabolism, and hormonal signaling. Phytohormonal analysis indicated that SV-mediated responses were, in part, modulated by specific alterations in phytohormone levels; especially salicylic acid (SA). Notably, several touch regulated genes were also up-regulated by SV treatment suggesting a possible molecular crosstalk among the two mechanical stimuli, sound and touch. Overall, these results provide a molecular basis to SV triggered global transcriptomic, proteomic and hormonal changes in plant.
Mitochondria are energy-generating organelles and mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular stimuli, including exercise. However, the mechanisms ...underlying mitochondrial biogenesis remain unknown. Here, we demonstrate that transcriptional coactivator with PDZ-binding motif (TAZ) stimulates mitochondrial biogenesis in skeletal muscle. In muscle-specific TAZ-knockout (mKO) mice, mitochondrial biogenesis, respiratory metabolism, and exercise ability were decreased compared to wild-type mice. Mechanistically, TAZ stimulates the translation of mitochondrial transcription factor A via Ras homolog enriched in brain (Rheb)/Rheb like 1 (Rhebl1)-mTOR axis. TAZ stimulates Rhebl1 expression via TEA domain family transcription factor. Rhebl1 introduction by adeno-associated virus or mTOR activation recovered mitochondrial biogenesis in mKO muscle. Physiologically, mKO mice did not stimulate exercise-induced mitochondrial biogenesis. Collectively, our results suggested that TAZ is a novel stimulator for mitochondrial biogenesis and exercise-induced muscle adaptation.
UVB has been shown to stimulate the generation of reactive oxygen species (ROS), which subsequently results in the activation of various intracellular signalling pathways and transcription factors ...(AP‐1, NF‐κB). These transcription factors are regulated by MAPKs, which increase cytokine and MMP expression. We examined the preventive effects of reversine on MMP‐1 and MMP‐3 expressions in NHEKs and NHDFs exposed to UVB irradiation. Also, we confirmed that reversine decreased pro‐inflammatory cytokine expression in NHEKs. The mechanism underlying the MMP inhibitory effects of reversine occurred via the suppression of UVB‐induced ROS generation and MAPK/AP‐1 activation. Therefore, reversine is an effective therapeutic candidate for preventing skin photoageing.
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