SLC34A2 promotes cell proliferation by activating STX17-mediated autophagy in esophageal squamous cell carcinoma.

BACKGROUND: Solute carrier family 34 member 2 (SLC34A2) has been implicated in the development of various malignancies. However, the clinical significance and underlying molecular mechanisms of SLC34A2 in esophageal squamous cell carcinoma (ESCC) remain elusive. METHODS: Western blotting, quantitative real-time PCR and immunohistochemistry were utilized to evaluate the expression levels of SLC34A2 mRNA/protein in ESCC cell lines or tissues. Kaplan-Meier curves were employed for survival analysis. CCK-8, colony formation, EdU and xenograft tumor model assays were conducted to determine the impact of SLC34A2 on ESCC cell proliferation. Cell cycle was examined using flow cytometry. RNA-sequencing and enrichment analysis were carried out to explore the potential signaling pathways. The autophagic flux was evaluated by western blotting, mRFP-GFP-LC3 reporter system and transmission electron microscopy. Immunoprecipitation and mass spectrometry were utilized for identification of potential SLC34A2-interacting proteins. Cycloheximide (CHX) chase and ubiquitination assays were conducted to test the protein stability. RESULTS: The expression of SLC34A2 was significantly upregulated in ESCC and correlated with unfavorable clinicopathologic characteristics particularly the Ki-67 labeling index and poor prognosis of ESCC patients. Overexpression of SLC34A2 promoted ESCC cell proliferation, while silencing SLC34A2 had the opposite effect. Moreover, SLC34A2 induced autophagy to promote ESCC cell proliferation, whereas inhibition of autophagy suppressed the proliferation of ESCC cells. Further studies showed that SLC34A2 interacted with an autophagy-related protein STX17 to promote autophagy and proliferation of ESCC cells by inhibiting the ubiquitination and degradation of STX17. CONCLUSIONS: These findings indicate that SLC34A2 may serve as a prognostic biomarker for ESCC.

EGCG-LYS Fibrils-Mediated CircMAP2K2 Silencing Decreases the Proliferation and Metastasis Ability of Gastric Cancer Cells in Vitro and in Vivo.

Aberrant expression of circular RNAs (circRNAs) has been reported to play an important biological regulatory role in gastric cancer (GC). For the purpose of silencing cancer-related genes, a new approach for cancer treatment using nanocarriers to deliver siRNA has been proposed. In this study, abundantly expressed circMAP2K2 (hsa_circRNA_102415) is identified in GC cells. CircMAP2K2 regulates the PCBP1/GPX1 axis through proteasome-mediated degradation, which further mediates the activation of the AKT/GSK3ß/epithelial-to-mesenchymal transition (EMT) signaling pathway and enhances the proliferation and metastatic ability of GC cells. To establish novel GC treatment, epigallocatechin-3-gallate-lysozyme (EGCG-LYS) fibrils are synthesized, and in vitro experiments demonstrate that EGCG-LYS has a higher siRNA delivery efficiency than Lipofectamine 2000 (lipo2000), which effectively silences the expression of circMAP2K2. Further studies show that EGCG-LYS carrying siRNA can successfully achieve lysosome escape, which allows it to be located in the cytoplasm to achieve post-transcriptional gene silencing. In addition, EGCG-LYS carrying si-circMAP2K2 has good circulating stability, excellent biosafety and antitumor ability in vivo. The EGCG-LYS fibrils delivery system provides a new tool and approach for the treatment of GC.

HER2-targeting antibody-drug conjugate RC48 alone or in combination with immunotherapy for locally advanced or metastatic urothelial carcinoma: a multicenter, real-world study.

BACKGROUND: Phase II trials showed the efficacy of anti-HER2 RC48-ADC (disitamab vedotin) for HER2-positive metastatic urothelial carcinoma (UC). This study evaluated RC48 alone verses in combination with immunotherapy for locally advanced or metastatic UC using real-world data. METHODS: This retrospective, multicenter, real-world study included patients with locally advanced or metastatic UC who received RC48 in five hospitals in China between July 2021 and April 2022. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events. RESULTS: Thirty-six patients were included. The patients were 47-87 years, and 26 (72.2%) were male. Eighteen patients received RC48 alone, and 18 received RC48 combined with a programmed death-1 antibody. The median PFS was 5.4 months. The median OS was not reached. The 6-month and 1-year PFS rates were 38.8% and 15.5%, respectively. The 1-year OS rate was 79.6%. Fourteen (38.9%) patients achieved a partial response, and the ORR was 38.9%. Eleven patients had stable disease, and the DCR was 69.4%. The median PFS for patients who received RC48 combined with immunotherapy and those who received RC48 alone was 8.5 and 5.4 months, respectively. The main treatment-related adverse events included anemia, hypoesthesia, fatigue, and elevated transaminase. No treatment-related death occurred. CONCLUSION: RC48 alone or combined with immunotherapy might benefit patients with locally advanced or metastatic UC, regardless of impaired renal function.

MCPIP1 Suppresses the NF-κB Signaling Pathway Through Negative Regulation of K63-Linked Ubiquitylation of TRAF6 in Colorectal Cancer.

The abnormal activation of the nuclear factor-kappa B (NF-κB) signaling pathway is an important precipitating factor for the inception and development of colorectal cancer (CRC), one of the most common tumors worldwide. As a pro-apoptotic transcription factor, monocyte chemotactic protein-induced protein 1 (MCPIP1) has been closely associated with many tumor types. In the present study, the expression of MCPIP1 was firstly discovered reduced in CRC tissues and correlated with poor patient prognosis. The decreased expression was caused by promoter hypermethylation. Overexpressed MCPIP1 was found to inhibit the proliferative and migratory abilities of CRC cells, whereas knockdown of MCPIP1 produced the opposite result. The subsequent investigation demonstrated that MCPIP1 exerted its "anti-cancer" effect by suppression of the NF-κB signaling pathway through negative regulation of K63-linked ubiquitylation of TNF receptor associated factor 6 (TRAF6). Therefore, our results indicate a prognostic marker for CRC and a theoretical basis for MCPIP1 as a treatment.

Overexpression of GNA13 correlates with poor prognosis in esophageal squamous cell carcinoma after esophagectomy.

BACKGROUND: This study aimed to explore the expression and clinical implication of guanine nucleotide-binding protein alpha 13 (GNA13) in esophageal squamous cell carcinoma (ESCC). METHODS: We first employed western blot analysis to test the GNA13 protein expression level in ESCC tissues. Subsequently, we used immunohistochemistry assays to detect the GNA13 in ESCC specimens from 173 patients who underwent esophagectomy. Survival analysis was performed to define the impact of GNA13 expressions on the prognosis of the ESCC patients based on the clinical and follow-up data. RESULTS: The GNA13 protein was shown to be considerably higher in ESCC tissues than in normal esophageal tissues. The level of expression was closely related to the tumor, node, TNM stage, and tumor size. More importantly, ESCC patients with high GNA13 expression carried an increased risk of tumor recurrence compared to those with low GNA13 expression. In addition, a high GNA13 expression level could independently predict worse overall survival and disease-free survival in ESCC. CONCLUSIONS: GNA13 could be a novel prognostic biomarker for ESCC patients after esophagectomy.

Chitosan-Gelatin-EGCG Nanoparticle-Meditated LncRNA TMEM44-AS1 Silencing to Activate the P53 Signaling Pathway for the Synergistic Reversal of 5-FU Resistance in Gastric Cancer.

Chemoresistance is one of the leading causes of therapeutic failure in gastric cancer (GC) treatment. Recent studies have shown lncRNAs play pivotal roles in regulating GC chemoresistance. Nanocarriers delivery of small interfering RNAs (siRNAs) to silence cancer-related genes has become a novel approach to cancer treatment research. However, finding target genes and developing nanosystems capable of selectively delivering siRNAs for disease treatment remains a challenge. In this study, a novel lncRNA TMEM44-AS1 that is related to 5-FU resistance is identified. TMEM44-AS1 has the ability to bind to and sponge miR-2355-5p, resulting in the upregulated PPP1R13L expression and P53 pathway inhibition. Next, a new nanocarrier called chitosan-gelatin-EGCG (CGE) is developed, which has a higher gene silencing efficiency than lipo2000, to aid in the delivery of a si-TMEM44-AS1 can efficiently silence TMEM44-AS1 expression to synergistically reverse 5-FU resistance in GC, leading to a markedly enhanced 5-FU therapeutic effect in a xenograft mouse model of GC. These findings indicate that TMEM44-AS1 may estimate 5-FU therapy outcome among GC cases, and that systemic si-TMEM44-AS1 delivery combined with 5-FU therapy is significant in the treatment of patients with recurrent GC.

Case Report: Prompt Response to Savolitinib in a Case of Advanced Gastric Cancer With Bone Marrow Invasion and MET Abnormalities.

Gastric cancer is one of the most common malignant tumors and patients show a short survival, those combined with bone marrow invasion have a median survival of only 37 days. Here we reported the treatment of a 47-year-old male with advanced gastric cancer and complicated with bone marrow invasion and extensive metastases, who did not tolerate chemotherapy, under monotherapy with savolitinib, a MET receptor tyrosine kinase inhibitor. Before treatment, the patient was in severe pain and presented with thrombocytopenia and hemorrhagic anemia. Savolitinib was given based on amplification and rearrangement of the MET gene in his tumor. After savolitinib treatment, the patient's condition promptly improved, efficacy evaluation indicated partial remission, and the patient was alive and remained progression-free at 15 weeks at the time of reporting. No obvious adverse reactions occurred. Besides, another case of a female gastric cancer patient with MET amplification who received savolitinib monotherapy as a third-line treatment that remained progression-free at 12 weeks was also reported. This report provides a new reference for understanding MET abnormalities in gastric cancer and offers a possibility for future application of MET tyrosine kinase inhibitors in the therapy of gastric cancer with MET abnormalities. Also, it suggests that sequencing of MET can be considered a routine target in advanced gastric cancer patients.

Treatment Outcome of Different Chemotherapy in Patients With Relapsed or Metastatic Malignant Urachal Tumor.

BACKGROUND: Malignant urachal tumor is a rare subtype of genitourinary cancer. Our aim was to explore the optimal chemotherapy regimens for relapsed or metastatic urachal carcinoma. MATERIALS AND METHODS: We retrospectively enrolled 24 adult patients with relapsed or metastatic urachal carcinoma from January 2014 to September 2020 at Sun Yat-sen University Cancer Center. We summarized the chemotherapy regimens and classified them as fluorouracil based, platinum based, and paclitaxel based. Nine patients received XELOX (capecitabine and oxaliplatin) regimens, seven patients received TX (paclitaxel and capecitabine) regimens, and eight of them received chemotherapy including GP (gemcitabine and cisplatin), TP (paclitaxel and cisplatin), TN (paclitaxel and nedaplatin), and tislelizumab. RESULTS: The disease control rate was 75%. Among all patients, one patient treated with XELOX achieved partial remission (PR), while 17 patients showed stable disease. The median progression-free survival (PFS) and overall survival (OS) in all treated patients was 7.43 and 29.7 months, respectively. The patients receiving first-line platinum-based chemotherapy presented better PFS than those without platinum (median PFS 8.23 vs. 3.80 months, p = 0.032), but not significant for OS between two groups. There is no significant difference in PFS and OS for fluorouracil-based and paclitaxel-based groups as first-line regimen. Next-generation gene sequencing revealed TP53 mutation and low tumor mutational burden in five out of seven cases. CONCLUSION: The platinum-based chemotherapy regimen is effective for relapsed or metastatic urachal carcinoma.