The tRNA-derived small RNAs (tsRNAs) are produced in a nuclease-dependent manner in responses to variety of stresses that are common in cancers. We focus on a cancer-enriched tsRNA signature to ...develop a salivary exosome-based non-invasive biomarker for human esophageal squamous cell carcinoma (ESCC).
Cancer-enriched small RNAs were identified by RNA sequencing of salivary exosomes obtained from ESCC patients (n = 3) and healthy controls (n = 3) in a pilot study and further validated in discovery cohort (n = 66). A multicenter prospective observational study was conducted in two ESCC high-incidence regions (n = 320 and 200, respectively) using the newly developed biomarker signature.
The tsRNA (tRNA-GlyGCC-5) and a previously undocumented small RNA were specifically enriched in salivary exosomes of ESCC patients, ESCC tissues and ESCC cells. The bi-signature composed of these small RNAs was able to discriminate ESCC patients from the controls with high sensitivity (90.50%) and specificity (94.20%). Based on the bi-signature Risk Score for Prognosis (RSP), patients with high-RSP have both shorter overall survival (OS) (HR 4.95, 95%CI 2.90-8.46) and progression-free survival (PFS) (HR 3.69, 95%CI 2.24-6.10) than those with low-RSP. In addition, adjuvant therapy improved OS (HR 0.47, 95%CI 0.29-0.77) and PFS (HR 0.36, 95%CI 0.21-0.62) only for patients with high but not low RSP. These findings are consistent in both training and validation cohort.
The tsRNA-based signature not only has the potential for diagnosis and prognosis but also may serve as a pre-operative biomarker to select patients who would benefit from adjuvant therapy.
A prospective study of diagnosis biomarkers of esophageal squamous cell carcinoma, ChiCTR2000031507 . Registered 3 April 2016 - Retrospectively registered.
Twist, the basic helix-loop-helix transcription factor, is involved in the process of epithelial to mesenchymal transitions (EMTs), which play an essential role in cancer metastasis. Overexpression ...of Twist or its promoter methylation is a common scenario in metastatic carcinomas. Twist is activated by a variety of signal transduction pathways, including Akt, signal transducer and activator of transcription 3, mitogen-activated protein kinase, Ras, and Wnt signaling. Activated Twist upregulates N-cadherin and downregulates E-cadherin, which are the hallmarks of EMT. Moreover, Twist plays an important role in some physiological processes involved in metastasis, like angiogenesis, invadopodia, extravasation, and chromosomal instability. Twist also protects cancer cells from apoptotic cell death. In addition, Twist is responsible for the stemness of cancer cells and the generation of drug resistance. Recently, targeting Twist has gained significant interests in cancer therapeutics. The inactivation of Twist by small RNA technology or chemotherapeutic approach has been proved successful. Moreover, several inhibitors which are antagonistic to the upstream or downstream molecules of Twist signaling pathways have also been identified. Development of potential treatment strategies by targeting Twist has a great promise in cancer therapeutics.
Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in ...prostate cancer.
By using TRAMP mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer.
Treating TRAMP mice with metformin delays prostate cancer progression from LGPIN to HGPIN, WD to UD, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after ADT induced by surgically castration in mice, bicalutamide treatment in patients and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells.
Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment.
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Lung cancer is the most commonly diagnosed cancer worldwide and it is also the most leading cause of cancer-related deaths. Although multiple generations of targeted therapeutic drugs ...such as gefitinib and afatinib specifically targeting the epidermal growth factor receptor (EGFR) pathway are currently available for lung cancer treatment, none of them can escape their eventual drug-resistance. As a key component of Cordyceps Sinensis and widely used in traditional Chinese medicines (TCM), cordycepin (CD) has attracted increasing attention to both scientists and clinicians. We aimed to explore the potential in developing cordycepin (CD) as an anti-lung cancer drug. A systematic analysis was conducted on a panel of non-small cell lung cancer (NSCLC) cell lines to identify the cells sensitive to CD. We found that CD can affect different aspects of lung cancer development including proliferation, migration, invasion, cell cycle, and apoptosis. We then explored the underlying molecular mechanisms of CD-mediated NSCLC cell apoptosis by conducting a series of in vitro and in vivo experiments. We found that in addition to affecting different stages of NSCLC development including tumor growth, migration, and invasion, the CD is capable of inhibiting NSCLC cell cycle progression and inducing cancer cell apoptosis without apparent adverse effect on normal lung cells. Furthermore, we found that the cells containing EGFR mutations are more sensitive to CD treatment than those without. Mechanistically, CD induces NSCLC cell apoptosis by interacting with and activating AMP-activated protein kinase (AMPK). More importantly, we found that the potency of CD’s anticancer effect both in vitro and in vivo is comparable to afatinib and even better than gefitinib. Our findings suggest that CD either by itself or in combination with the currently available targeted therapeutic drugs might be additional therapeutic options for drug-resistance NSCLC treatment.
Post-translational modification of chromatin has profound effects on many biological processes including transcriptional regulation, heterochromatin organization, and X-chromosome inactivation. ...Recent studies indicate that methylation on specific histone lysine (K) residues participates in many of these processes. Lysine methylation occurs in three distinct states, having either one (me1), two (me2) or three (me3) methyl groups attached to the amine group of the lysine side chain. These differences in modification state have an important role in defining how methylated chromatin is recognized and interpreted. Until recently, histone lysine methylation was considered a stable modification, but the identification of histone demethylase enzymes has demonstrated the reversibility of this epigenetic mark. So far, all characterized histone demethylases show enzymatic activity towards lysine residues modified in the me1 or me2 state, leaving open the possibility that me3 constitutes an irreversible modification. Here we demonstrate that JHDM3A (jumonji C (JmjC)-domain-containing histone demethylase 3A; also known as JMJD2A) is capable of removing the me3 group from modified H3 lysine 9 (H3K9) and H3 lysine 36 (H3K36). Overexpression of JHDM3A abrogates recruitment of HP1 (heterochromatin protein 1) to heterochromatin, indicating a role for JHDM3A in antagonizing methylated H3K9 nucleated events. siRNA-mediated knockdown of JHDM3A leads to increased levels of H3K9 methylation and upregulation of a JHDM3A target gene, ASCL2, indicating that JHDM3A may function in euchromatin to remove histone methylation marks that are associated with active transcription.
Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4-6 ...months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice bearing CWR22Rv1 xenografts treated with either enzalutamide or metformin alone or in combination, we demonstrated that metformin is capable of reversing enzalutamide resistance and restores sensitivity of CWR22Rv1 xenografts to enzalutamide. We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT. Furthermore, based on the effect of metformin on the activation of STAT3 and expression of TGF-β1, we propose that metformin exerts its effects by targeting the TGF-β1/STAT3 axis. These findings suggest that combination of metformin with enzalutamide could be a more efficacious therapeutic strategy for the treatment of castration-resistant prostate cancer.
Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, ...nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.
Lung cancer is a serious health problem and the leading cause of cancer death worldwide, due to its high incidence and mortality. 85% of lung cancers are represented by the non-small cell lung cancer ...(NSCLC). Traditional chemotherapy has been the main treatment option in NSCLC. However, it is often associated with limited efficacy and overall poor patient survival. In recent years, molecular targeting has achieved great progress in therapeutic treatment of cancer and plays a crucial role in the current clinical treatment of NSCLC, due to enhanced efficacy on cancer tissues and reduced toxicity for normal tissues. In this review, we summarize the current targeting treatment of NSCLC, including inhibition of the epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3Ks), mechanistic target of rapamycin (mTOR), epidermal growth factor receptor 2 (ErbB2), vascular epidermal growth factor receptor (VEGFR), kirsten human rat sarcoma protein (KRAS), mesenchymal-epithelial transition factor or hepatocyte growth factor receptor (c-MET), anaplastic lymphoma kinase (ALK), v-Raf murine sarcoma viral oncogene homolog B (BRAF). This article may serve as a guide to clinicians and researchers alike by assisting in making therapeutic decisions. Challenges of acquired drug resistance targeted therapy and imminent newer treatment modalities against NSCLC are also discussed.
Regulation, targets and functions of CSK Zhu, Shudong; Wang, Hui; Ranjan, Kamakshi ...
Frontiers in cell and developmental biology,
06/2023, Volume:
11
Journal Article
Peer reviewed
Open access
The Src family kinases (SFK) plays an important role in multiple signal transduction pathways. Aberrant activation of SFKs leads to diseases such as cancer, blood disorders, and bone pathologies. By ...phosphorylating and inactivating SFKs, the C-terminal Src kinase (CSK) serves as the key negative regulator of SFKs. Similar to Src, CSK is composed of SH3, SH2, and a catalytic kinase domain. However, while the Src kinase domain is intrinsically active, the CSK kinase domain is intrinsically inactive. Multiple lines of evidence indicate that CSK is involved in various physiological processes including DNA repair, permeability of intestinal epithelial cells (IECs), synaptic activity, astrocyte-to-neuron communication, erythropoiesis, platelet homeostasis, mast cell activation, immune and inflammation responses. As a result, dysregulation of CSK may lead to many diseases with different underlying molecular mechanisms. Furthermore, recent findings suggest that in addition to the well-established CSK-SFK axis, novel CSK-related targets and modes of CSK regulation also exist. This review focuses on the recent progress in this field for an up-to-date understanding of CSK.
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