Serine metabolism is a critical vulnerability in cancer; however, its role in mediating therapeutic resistance in non-small cell lung cancer (NSCLC) remains incompletely understood. In this study, we identify key enzymes in the serine synthesis pathway (SSP), namely PHGDH, PSAT1 and PSPH, as well as the serine transporter SLC1A4, which are significantly overexpressed in lung cancer and correlate with poor patient prognosis. We show that serine contributes to carboplatin resistance in NSCLC, particularly in lung squamous cell carcinoma (LUSC). Notably, the LUSC lineage-specific oncogene ΔNp63α serves as a master transcriptional regulator of serine biosynthesis, directly transactivating the expression of PHGDH, PSAT1, PSPH, and SLC1A4. ΔNp63α-driven serine biosynthesis supports nucleotide synthesis and enhances antioxidant defense, enabling cancer cells to survive carboplatin-induced DNA damage and oxidative stress, thereby promoting therapeutic resistance. The combined inhibition of endogenous serine synthesis and restriction of exogenous serine/glycine significantly overcomes ΔNp63α-mediated carboplatin resistance. Our findings establish the ΔNp63α-SSP axis as a critical mechanism driving carboplatin resistance in LUSC. These results highlight dual-targeted disruption of serine availability as a promising therapeutic strategy to overcome chemotherapy resistance in ΔNp63α-driven LUSC. This study underscores the importance of lineage-specific metabolic dependencies as essential targets for precision oncology in NSCLC.

The rat sarcoma virus oncogene (RAS) is one of the most frequently mutated drivers in human cancers. Developing targeted therapies against RAS has been challenging due to its structure. The recent breakthroughs with covalent Kirsten RAS (KRAS) inhibitors represent a key milestone in targeting mutant KRAS proteins. However, drug resistance remains a significant obstacle. The proteolysis-targeting chimeras (PROTACs), which degrade mutant KRAS proteins, offer a promising strategy to overcome resistance and expand therapeutic options. This review covers the structural basis of KRAS and signaling networks, while discussing recent advancements in KRAS inhibitor research and PROTAC technology. It aims to provide a foundation and inspiration for future KRAS inhibitor and degrader development.

Endoplasmic reticulum (ER) stress is increasingly recognized as a driver of cancer progression; however, the precise molecular mechanisms by which ER stress facilitates tumor metastasis remain incompletely understood. In this study, we demonstrate that ER stress-activated ATF6α promotes breast cancer cell migration and metastasis by downregulating the expression of ΔNp63α, a key metastasis suppressor. Mechanistically, ATF6α reduces ΔNp63α expression through GRP78, which interacts with and activates AKT1. Activated AKT1 subsequently phosphorylates FOXO3a, leading to its degradation. Since FOXO3a directly transactivates ΔNp63α expression, its degradation results in reduced ΔNp63α levels. Furthermore, pharmacological inhibition or genetic knockdown of AKT1 upregulates ΔNp63α in vitro and suppresses tumor metastasis in vivo. Clinical analyses reveal that TP63 and FOXO3a expression are significantly reduced in breast cancer tissues compared to normal tissues, whereas ATF6 and GRP78 expression are elevated. Moreover, low TP63 and high GRP78 expression are associated with a poor prognosis in breast cancer patients. Collectively, these findings elucidate the pivotal role of the ATF6α-GRP78-AKT1-FOXO3a axis in chronic ER stress-mediated downregulation of ΔNp63α, establishing a molecular framework for targeting this pathway as a potential therapeutic strategy against breast cancer metastasis.

OBJECTIVE:Current cisplatin (CDDP) resistance remains a major challenge in the treatment of advanced gastric cancer. To address the issue of drug resistance, we explored the regulatory functions of PDZ and LIM structural domain protein 1 (PDLIM1) in CDDP chemotherapy for gastric cancer. METHODS:In this study, we analyzed PDLIM1 expression and prognosis using bioinformatics on publicly available data. PDLIM1 expression in a gastric mucosal epithelial cell line (GSE-1), CDDP- sensitive (SGC7901, BGC823) and CDDP-resistant gastric cancer cells was detected by RTqPCR and Western blotting. Cell proliferative capacity was assessed by knockdown of PDLIM1 and overexpression of PDLIM1 in cells administered in combination with cisplatin, and apoptotic levels were measured by CCK-8 and colony formation assay and by flow cytometry. Expression of breast cancer susceptibility gene 1 (BRCA1) and γH2AX was determined by Western blotting or immunofluorescence staining. RESULTS:Downregulation of PDLIM1 was found in tumor tissues and cells, which was associated with poor clinical outcomes. Knockdown of PDLIM1 enhanced proliferation and attenuated apoptosis in gastric cancer cells. In addition, the therapeutic effects of CDDP on proliferation, apoptosis, and DNA damage repair were attenuated by PDLIM1 deletion.PDLIM1 expression was downregulated in CDDP-resistant tumor cells. Overexpression of PDLIM1 overcomes CDDP resistance in tumor cells as BRCA1 expression decreases and γH2AX expression increases. CONCLUSION:Our findings demonstrate that PDLIM1 enables to alleviate gastric cancer progression and resistance to cisplatin via impeding DNA damage repair.

PURPOSE:Gastric cancer (GC) is the fifth leading cancer around world. And prognosis of patients with GC is still undesirable. Our study aimed to explore potential prognostic biomarkers for patients with GC.METHODS:The clinical samples were collected from the Qinghai University Affiliated Hospital, which were subjected to the whole exome sequencing (WES). The other GC-related data were obtained from The Cancer Genome Atlas (TCGA) database. Cross analyses were done to determine the candidate genes. And the final mutated genes were determined by survival analyses, univariate and multivariate Cox regression analyses. CIBERSORT and GSEA were used for immune cell infiltration analysis and functional enrichment, respectively.RESULTS:After cross analyses, 160 candidate-mutated genes were identified. And mutated ELP6 and PLIN5 were significantly independently correlated with the overall survival (OS) of patients with GC. Patients with GC with ELP6 and PLIN5 mutations had worse and better prognosis, respectively. Totally 5 types of immune cells were significantly differentially infiltrated in wild-type and mutated ELP6 and PLIN5 GC samples. In mutated ELP6 and PLIN5 GC samples, totally 7 and 11 pathways were significantly enriched, respectively.CONCLUSIONS:The ELP6 and PLIN5 mutations were probably prognostic biomarkers for patients with GC.

Gastric cancer is the most common digestive tract malignancy in China and has a poor prognosis, with a 5-year overall survival rate of only 35.1%. Because its early symptoms are not obvious and early diagnosis is complicated, there is an urgent need to find biological targets for diagnosis and treatment. This research detected the expression of STAT3 in gastric cancer tissues and adjacent tissues by Western blot and immunohistochemical experiments and conducted corresponding basic experiments to explore the role of STAT3 in inhibiting the proliferation of cisplatin-resistant gastric cancer cells and promoting their apoptosis, including the construction of cisplatin-resistant gastric cancer cell line, the knock-out STAT3 in drug-resistant gastric cancer cells by CRISPR-Cas9, and the comparison of the proliferation and apoptosis of drug-resistant cells and drug-resistant cells STAT3(-). The mechanism provides a possible intervention target for clinically improving the prognosis of patients with cisplatin-resistant gastric cancer.

OBJECTIVE: Glioma and meningioma are the most common primary brain tumors in adults. Epidemiologic studies of the relationship between female hormone exposure and exogenous hormone use and the risk of meningioma and glioma in females have yielded inconsistent results. METHODS: Two investigators comprehensively searched 3 electronic databases, including PubMed, Embase, and Cochrane Library. A total of 11 case-control studies were enrolled for meta-analysis. Dose-response meta-analyses were conducted. RESULTS: Compared with the noneoral contraceptives (OCs) female users, the female OC users might have reduced risk of glioma (risk ratio [RR], 0.87; 95% confidence interval [CI], 0.77-0.97; I-2 = 42.6%). However, there was no obvious evidence of an association between OC use and the risk of meningioma in females (RR, 0.99; 95% CI, 0.87-1.13; I-2 = 42.7%). Using OCs for >10 years in females may significantly decrease the risk of glioma to 30% (RR, 0.7; 95% CI, 0.6-0.81; I-2 = 0%). The dose-response meta-analyses indicated that the risk of glioma in females significantly decreased when the duration of oral OC use was >7.5 years. CONCLUSIONS: OC use may not increase the risks of glioma and meningioma in females. Instead, the long-term use of OCs may significantly decrease the risk of glioma, and the benefits are even more pronounced when the time window is >7.5 years. Nonetheless, the pooled results in this study suggest that OC use may not increase the risk of meningioma. Therefore, our conclusion should be validated and supplemented in future larger studies.

BACKGROUND:Secreted protein acidic and rich in cysteine (SPARC) is always considered as a marker of poor prognosis. However, it helps to transport nab-paclitaxel and may lead better therapeutic ending. This meta-analysis was aimed to assess the relationship between SPARC expression level and clinical efficacy of nab-paclitaxel.METHODS:The PubMed and Embase databases were searched from inception to April 2020, and search terms included nanoparticle albumin-bound paclitaxel, nab-paclitaxel, nab-PTX, Abraxane, ABI-007, secreted protein acidic and rich in cysteine, SPARC, osteonectin, and BM-40. In addition, funnel plots were used to indicate the existence of publication bias.RESULTS:After further screening the full text, 5 studies that involved 336 patients were finally included in the study, of which, 3 studies concentrated on non-small cell lung cancer (NSCLC) and the other 2 on breast cancer and pancreatic cancer. SPARC status in tumor cells and stromal cells was taken into account. The HR for progression-free survival (PFS) between SPARC high and low groups was 1.25 (95% CI: 0.72-2.14, stromal cell) and 1.51 (95% CI: 0.93-2.46, tumor cell). The HR for OS between SPARC high and low groups was 1.07 (95% CI: 0.57-2.03, stromal cell) and 1.34 (95% CI: 0.74-2.43, tumor cell). It was revealed that SPARC expression level in tumor cells or stromal cells was not significantly correlated with the patient's survival outcomes. No significant publication bias was found in each analysis.CONCLUSIONS:SPARC expression level detected by immunohistochemistry (IHC) cannot predict the efficacy of nab-paclitaxel, while further large-scale clinical trials are required to confirm our findings.

In order to improve the corrosion resistance of zirconium alloy in high temperature and high pressure water environment, Cr/TiAlN coating and Cr/TiAlSiN coating were prepared on the surface of Zr-4 alloy by multi-arc ion plating (MAIP). The corrosion resistance of the two coatings in the autoclave was compared by various analytical methods:The film-based bonding force of the coating was detected by an automatic scratch test; the microstructure of the coating was observed by scanning electron microscope (SEM); the porosity and the quantity of large particles on the surface were analyzed by Image J software; the phase of the coating was analyzed by x-ray diffractometer (XRD); the type and content of the coating were detected by energy dispersive spectrometer (EDS). The experiment result shows that the surface of the two coatings is relatively flat, and the surface of the Cr/TiAlSiN coating is finer than that of the Cr/TiAlN coating, and the number of large particles is small and the density is high. The critical loads that the Cr/TiAlN coating and the Cr/TiAlSiN coating can withstand are 34 N and 29 N respectively. Under the experimental conditions, part of the Cr/TiAlN coating peeled off and localized corrosion occurred; A large amount of ZrO2 was detected on the surface of the sample, the coating was destroyed and the protective effect was lost. While, the Cr/TiAlSiN coating is almost intact, it effectively preventing the substrate from being corroded. In conclusion: the coating quality of multi-arc ion plating Cr/TiAlSiN coating is better than that of Cr/TiAlN coating, and the corrosion resistance is better. It can protect the zirconium alloy matrix effectively. However, the residual stress is generated due to the presence of Si in the Cr/TiAlSiN coating, which resulting in a low film-based bonding force.