<div>Abstract<p>ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the <i>mTOR</i> promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5–mTOR–CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment <i>in vivo</i> and <i>in vitro</i>. Our results suggest the existence of a ZEB1/KLF5–mTOR–CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis.</p>Implications:<p>This study highlights the function of haplotypes of <i>mTOR</i> -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5–mTOR–CCND1/ABCB1 axis.</p></div>
In recent years, to treat a diverse array of cancer forms, considerable advancements have been achieved in the field of cancer immunotherapies. However, these therapies encounter multiple challenges in clinical practice, such as high immune-mediated toxicity, insufficient accumulation in cancer tissues, and undesired off-target reactions. To tackle these limitations and enhance bioavailability, polymer micelles present potential solutions by enabling precise drug delivery to the target site, thus amplifying the effectiveness of immunotherapy. This review article offers an extensive survey of recent progress in cancer immunotherapy strategies utilizing micelles. These strategies include responsive and remodeling approaches to the tumor microenvironment (TME), modulation of immunosuppressive cells within the TME, enhancement of immune checkpoint inhibitors, utilization of cancer vaccine platforms, modulation of antigen presentation, manipulation of engineered T cells, and targeting other components of the TME. Subsequently, we delve into the present state and constraints linked to the clinical utilization of polymeric micelles. Collectively, polymer micelles demonstrate excellent prospects in tumor immunotherapy by effectively addressing the challenges associated with conventional cancer immunotherapies.
Abstract High mortality of patients with cervical cancer (CC) stresses the imperative of prognostic biomarkers for CC patients. Additionally, the vital status of post‐translational modifications (PTMs) in the progression of cancers has been reported by numerous researches. Therefore, the purpose of this research was to dig a prognostic signature correlated with PTMs for CC. We built a five‐mRNA (GALNTL6, ARSE, DPAGT1, GANAB and FURIN) prognostic signature associated with PTMs to predict both disease‐free survival (DFS) (hazard ratio [HR] = 3.967, 95% CI = 1.985‐7.927; P < .001) and overall survival (HR = 2.092, 95% CI = 1.138‐3.847; P = .018) for CC using data from The Cancer Genome Atlas database. Then, the robustness of the signature was validated using GSE44001 and the Human Protein Atlas (HPA) database. CIBERSORT algorithm analysis displayed that activated CD4 memory T cell was also an independent indicator for DFS (HR = 0.426, 95% CI = 0.186‐0.978; P = .044) which could add additional prognostic value to the signature. Collectively, the PTM‐related signature and activated CD4 memory T cell can provide new avenues for the prognostic predication of CC. These findings give further insights into effective treatment strategies for CC, providing opportunities for further experimental and clinical validations.
The expression of TNF-like weak inducer of apoptosis (TWEAK) in breast cancer remains disputable. This study was to investigate the expression of TWEAK in breast cancer tissues and breast cancer cell lines with different invasive abilities, and the relationship of TWEAK with microvessel density (MVD).Immunohistochemical S-P method was adopted to detect the expression of TWEAK in 70 specimens of breast cancer and 30 specimens of adjacent normal breast tissues. The protein expression of TWEAK was determined by Western blot in a poorly invasive breast cancer cell line MCF-7 and a highly invasive breast cell line MDA-MB-231. Secretion of TWEAK was measured by ELISA assay in MCF-7 and MDA-MB-231 cells.The expression of TWEAK was higher in breast cancer (60%) than in adjacent normal breast tissues( 6.67%) (P<0.05), and is higher in infiltrating ductal carcinoma of the breast (76.67 %) than in breast ductal carcinoma in situ (42.85%) (P=0.003). MVD was higher in infiltrating ductal carcinoma of the breast than in breast ductal carcinoma in situ (P<0.05). The expression of TWEAK was significantly correlated with MVD in infiltrating ductal carcinoma of the breast(r=0.611), but not with breast ductal carcinoma in situ (r=0.015). The expression of TWEAK and secretion of soluble TWEAK were higher in MDA-MB-231 cells than in MCF-7 cells (t=4.259, P=0.007; t=3.6504, P=0.006 ).TWEAK expression is related to the metastatic ability of breast cancer.
OBJECTIVE:To study the effects of selective K+ channel blocker 4-AP on the action of DOC inhibits human breast cancer cell MDA-MB-435S on the cell proliferation,apoptosis and cell cycle.METHODS:The effects of DOC,4-AP and the combination of both drugs on proliferation of MDA-MB-435S cell were investigated by MTT assays.The apoptosis cells and cell cycles were measured by flow cytometry after the cells were stained by both Annexin-V and PI and PI only,respectively.RESULTS:DOC and 4-AP inhibited the proliferation of human breast cancer cell MDA-MB-435S,respectively.4-AP of 5 mmol/L advanced the time of DOC of 25 μmol/L inducing human breast cancer cell MDA-MB-435S to the maximum inhibitory rate.DOC and 4-AP had additive or synergetic effects on inhibiting the proliferation of MDA-MB-435S,and the effects presented the time-dose dependence.The effects of improving MDA-MB-435S cell apoptosis were not obvious when given DOC of 2 μmol/L or 5 μmol/L for 24 hours,but when DOC were combined with 4-AP of 5 mmol/L,both the pristine cell apoptosis and the cell death were very transparent.MDA-MB-435S cells were blocked at G2/M period by DOC,they were blocked at G0/G1 period by 4-AP,and they were blocked at G2/M period when using both DOC and 4-AP.CONCLUSIONS:DOC and 4-AP can inhibit human breast cancer cell MDA-MB-435S proliferation by blocking cells at G2/M period and G0/G1 period,respectively.4-AP can inhibit MDA-MB-435S proliferation by improving cell apoptosis induced by DOC.
Abstract Gastric cancer (GC) is one of the most fatal common cancers in worldwide. Helicobacter pylori ( H. pylori ) infection is closely related to the development of GC, although the mechanism is still unclear. In our study, we aim to develop a robust messenger RNA (mRNA) signature associated with H. pylori (‐) GC that can sensitively and efficiently predict the prognostic. The RNA‐seq expression profile and corresponding clinical data of 598 gastric cancer samples and 63 normal samples obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. Using gene set enrichment analysis H. pylori (+) GC and H. pylori (‐) GC patients and normal samples to select certain genes for further analysis. Using univariate and multivariate Cox regression model to establish a gene signature for predicting the overall survival (OS). Finally, we identified G2/M related seven‐mRNA signature ( TGFB1, EGF, MKI67, ILF3, INCENP, TNPO2 , and CHAF1A ) closely related to the prognosis of patients with H. pylori (‐) GC. The seven‐mRNA signature was identified to act as an independent prognostic biomarker by stratified analysis and multivariate Cox regression analysis. It was also validated on two test groups from TCGA and GSE15460 and shown that patients with high‐risk scores based on the expression of the seven mRNAs had significantly shorter survival times compared to patients with low‐risk scores ( P < .0001). In this study, we developed a seven‐mRNA signature related to G2/M checkpoint from H. pylori (‐) GCs that as an independent biomarker potentially with a good performance in predicting OS and might be valuable for the clinical management for patients with GC.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
