Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAMs in colorectal cancer are contradictory. We therefore investigated the ...functions, mechanisms, and clinical significance of TAMs in colorectal cancer.
We measured the macrophage infiltration (CD68), P-gp, and Bcl2 expression in colorectal cancer tissues using IHC staining. Coculture of TAMs and colorectal cancer cells both
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models was used to evaluate the effects of TAMs on colorectal cancer chemoresistance. Cytokine antibody arrays, ELISA, neutralizing antibody, and luciferase reporter assay were performed to uncover the underlying mechanism.
TAM infiltration was associated with chemoresistance in patients with colorectal cancer. Colorectal cancer-conditioned macrophages increased colorectal cancer chemoresistance and reduced drug-induced apoptosis by secreting IL6, which could be blocked by a neutralizing anti-IL6 antibody. Macrophage-derived IL6 activated the IL6R/STAT3 pathway in colorectal cancer cells, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-204-5p. Rescue experiment confirmed that miR-204-5p is a functional target mediating the TAM-induced colorectal cancer chemoresistance. miR-155-5p, a key miRNA regulating C/EBPβ, was frequently downregulated in TAMs, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL6 in TAMs, and TAM-secreted IL6 then induced chemoresistance by activating the IL6R/STAT3/miR-204-5p pathway in colorectal cancer cells.
Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL6 signaling in TAMs could induce chemoresistance in colorectal cancer cells by regulating the IL6R/STAT3/miR-204-5p axis, revealing a new cross-talk between immune cells and tumor cells in colorectal cancer microenvironment.
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Recent preliminary studies reported the in vitro tumor-promoting effects of long non-coding RNA urothelial carcinoma associated 1 (UCA1) in colorectal cancer (CRC). However, the in vivo functions and ...molecular mechanism of UCA1 in CRC remain unclear. Therefore, we investigated the detailed role and mechanism of UCA1 in CRC. We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Functional assays revealed the in vitro and in vivo growth-promoting function of UCA1 and revealed that UCA1 can decrease the sensitivity of CRC cells to 5-FU by attenuating apoptosis. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a highly aggressive subtype associated with poor prognosis. The advent of HER2-targeted drugs, including monoclonal ...antibodies, tyrosine-kinase inhibitors (TKIs) and antibody-drug conjugates, has yielded improved prognosis for patients. Compared with widely used monoclonal antibodies, small-molecule TKIs have unique advantages including oral administration and favorable penetration of blood-brain barrier for brain metastatic BC, and reduced cardiotoxicity. Pyrotinib is an irreversible TKI of the pan-ErbB receptor, and has recently been shown to be clinically effective for the treatment of HER2-positive BC in metastatic and neoadjuvant settings. This review highlights the development on the application of pyrotinib-based therapeutic approaches in the clinical settings of HER2-positive BC.
Automatic clutch control is critical in automated manual transmission systems because clutch actions have a significant influence on the vehicle performance, including safety, comfort, reliability, ...and shifting quality. However, clutch control is a challenging problem due to nonlinearity of throw-out force and uncertainty in clutch wear. For precise position control of the clutch, this study proposes a control scheme using model predictive control method with the correction of clutch wear based on the estimation of resistance torque. First, a novel and detailed clutch model is introduced, mainly including a driven plate model and a diaphragm spring model. Next, through theoretical analysis of the clutch model and the experimental data of a real clutch, the characteristics of the nonlinear throw-out force are obtained with different clutch wear situations. Then, a reliable clutch actuator is designed, whose model is also built to analyze its dynamics. At last, an automatic clutch controller is designed, and in order to apply it in clutch control unit for real-time control, it is simplified to reduce the online computing burden. The results both of simulations and bench experiments show that the proposed control scheme has a satisfying control performance.
Venous thromboembolism (VTE), is a noteworthy complication in individuals with gastric cancer, but the current diagnosis and treatment methods lack accuracy. In this study, we developed a t-PAIC ...chemiluminescence kit and employed chemiluminescence to detect the tissue plasminogen activator inhibitor complex (t-PAIC), thrombin-antithrombin III complex (TAT), plasmin-α2-plasmin inhibitor complex (PIC) and thrombomodulin (TM), combined with D-dimer and fibrin degradation products (FDP), to investigate their diagnostic potential for venous thrombosis in gastric cancer patients. The study assessed variations in six indicators among gastric cancer patients at different stages.
The t-PAIC reagent showed LOD is 1.2 ng/mL and a linear factor R greater than 0.99. The reagents demonstrated accurate results, with all accuracy deviations being within 5%. The intra-batch and inter-batch CVs for the t-PAIC reagent were both within 8%. The correlation coefficient R between this method and Sysmex was 0.979. Gastric cancer patients exhibited elevated levels of TAT, PIC, TM, D-D, FDP compared to the healthy population, while no significant difference was observed in t-PAIC. In the staging of gastric cancer, patients in III-IV stages exhibit higher levels of the six markers compared to those in I-II stages. The ROC curve indicates an enhancement in sensitivity and specificity of the combined diagnosis of four or six indicators.
Our chemiluminescence assay performs comparably to Sysmex's method and at a reduced cost. The use of multiple markers, including t-PAIC, TM, TAT, PIC, D-D, and FDP, is superior to the use of single markers for diagnosing VTE in patients with malignant tumors. Gastric cancer patients should be screened for the six markers to facilitate proactive prophylaxis, determine the most appropriate treatment timing, ameliorate their prognosis, decrease the occurrence of venous thrombosis and mortality, and extend their survival.
Adriamycin (ADM)‐based regimens are the most effective chemotherapeutic treatments for breast cancer. However, intrinsic and acquired chemoresistance is a major therapeutic problem. Our goal was to ...clarify the role of mediator complex subunit 19 (Med19) in chemotherapy resistance and to elucidate the related molecular mechanisms. In this study, ADM‐resistant human cells (MCF‐7/ADM) and tissues exhibited increased Med19 expression and autophagy levels relative to the corresponding control groups. Additionally, MCF‐7/ADM cells showed changes in two selective markers of autophagy. There was a dose‐dependent increase in the light chain 3 (LC3)‐II/LC3‐I ratio and a decrease in sequestosome 1 (P62/SQSTMl) expression. Furthermore, lentivirus‐mediated Med19 inhibition significantly attenuated the LC3‐II/LC3‐I ratio, autophagy‐related gene 3 (Atg3) and autophagy‐related gene 5 (Atg5) expression, P62 degradation, and red fluorescent protein‐LC3 dot formation after treatment with ADM or rapamycin, an autophagy activator. Furthermore, the antiproliferative effects of ADM, cisplatin (DDP), and taxol (TAX) were significantly enhanced after suppressing Med19 expression. Notably, the effects of Med19 on autophagy were mediated through the high‐mobility group box‐1 (HMGB1) pathway. Our findings suggest that Med19 suppression increased ADM chemosensitivity by downregulating autophagy through the inhibition of HMGB1 signaling in human breast cancer cells. Thus, the regulatory mechanisms of Med19 in autophagy should be investigated to reduce tumor resistance to chemotherapy.
Chemoresistance, the major obstacle in breast cancer chemotherapy, results in unnecessary chemotherapy and wasting of medical resources. No feasible method has been available to predict ...chemoresistance before chemotherapy. In our previous study, elevated expression of transient receptor potential channel TRPC5 was found to be an essential element for chemoresistance in breast cancer cells, and it was determined that it could be transferred to chemosensitive breast cancer cells through releasing extracellular vesicles (EV) containing TRPC5 from chemoresistant cells, resulting in acquired chemoresistance. Exosomes, a type of EV, are secreted membrane‐enclosed vesicles of 50–150‐nm diameter. In this study we found that circulating exosomes in peripheral blood from breast cancer patients carried TRPC5. In the present study, circulating exosome‐carrying TRPC5 (cirExo‐TRPC5) level was significantly correlated with TRPC5 expression level in breast cancer tissues and tumor response to chemotherapy. Furthermore, increased cirExo‐TRPC5 level after chemotherapy preceded progressive disease (PD) based on imaging examination and strongly predicted acquired chemoresistance. Taken together, our study demonstrated that cirExo‐TRPC5 might act as a noninvasive chemoresistance marker and might serve as an adjuvant to the current imaging examination‐based chemoresistance.
Increased cirExo‐TRPC5 level after chemotherapy was preceding progressive disease (PD) based on imaging examination and strongly predicted acquired chemoresistance. CrExo‐TRPC5 might act as a noninvasive chemoresistance marker and might serve as an adjuvant to the current imaging examination‐based chemoresistance.
Tumor is a local tissue hyperplasia resulted from cancerous transformation of normal cells under the action of various physical, chemical and biological factors. The exploration of tumorigenesis ...mechanism is crucial for early prevention and treatment of tumors. Epigenetic modification is a common and important modification in cells, including DNA methylation, histone modification, non-coding RNA modification and m6A modification. The normal mode of cell death is programmed by cell death-related genes; however, recent researches have revealed some new modes of cell death, including pyroptosis, ferroptosis, cuproptosis and disulfidptosis. Epigenetic regulation of various cell deaths is mainly involved in the regulation of key cell death proteins and affects cell death by up-regulating or down-regulating the expression levels of key proteins. This study aims to investigate the mechanism of epigenetic modifications regulating pyroptosis, ferroptosis, cuproptosis and disulfidptosis of tumor cells, explore possible triggering factors in tumor development from a microscopic point of view, and provide potential targets for tumor therapy and new perspective for the development of antitumor drugs or combination therapies.
5-Fluorouracil (5-Fu) is commonly used in the chemotherapy of colorectal cancer (CRC), but resistance to 5-Fu occurs in most cases, allowing cancer progression. Suppressing ABCB1 (ATP-binding ...cassette, subfamily B, member 1), which is a pump overproduced in cancer cells to export cytotoxic drugs, is an attractive strategy to overcome drug resistance. In the present study, transient receptor potential channel TrpC5 was found to be overproduced at the mRNA and protein levels together with ABCB1 in 5-Fu-resistant human CRC HCT-8 (HCT-8/5-Fu) and LoVo (LoVo/5-Fu) cells. More nuclear-stabilized β-catenin accumulation was found in HCT-8/5-Fu and LoVo/5-Fu cells than in HCT-8 and LoVo cells. Suppressing TrpC5 expression with TrpC5-specific siRNA inhibited the canonical Wnt/β-catenin signal pathway, reduced the induction of ABCB1, weakened the ABCB1 efflux pump, and caused a remarkable reversal of 5-Fu resistance in HCT-8/5-Fu and LoVo/5-Fu cells. On the contrary, enforcing TrpC5 expression resulted in an activated Wnt/β-catenin signal pathway and up-regulation of ABCB1. Taken together, we demonstrated an essential role of TrpC5 in ABCB1 induction and drug resistance in human CRC cells via promoting nuclear β-catenin accumulation.Resistance to 5-fluorouracil leads to the failure of chemotherapy for colorectal cancer.
Suppressing TrpC5 expression decreased nuclear β-catenin accumulation, reduced the induction of ABCB1, and reversed 5-fluorouracil resistance.
TrpC5 is essential in ABCB1 induction and drug resistance in human colorectal cancer cells.
These findings may help develop a novel target for overcoming resistance to chemotherapy in colorectal cancer.
Chirality is a fundamental characteristic of natural molecules and a crucial factor in the biochemical reactions of living cells and organisms. Recently, researchers have successfully introduced ...chiral molecules to the surfaces of nanomaterials, creating chiral nanomaterials that exhibit an upscaling of chiral behavior from the molecular scale to the nanoscale. These chiral nanomaterials can selectively induce autophagy, apoptosis, and photothermal ablation in tumor cells based on their chirality, making them promising for application in anti-tumor therapy. However, these interesting and important phenomena have hitherto received little attention. Accordingly, we herein present a review of recent research progress in the field of chiral nanomaterials for tumor therapy along with brief looks at the mechanistic details of their actions. Finally, the current challenges and future perspectives of chiral nanomaterials in terms of maximizing their potential in tumor therapy are discussed. Thus, this review provides a helpful introduction to the design of chiral nanomaterials and will hopefully highlight the importance of chirality in tumor therapy.
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