MicroRNA-495 Confers Increased Sensitivity to Chemotherapeutic Agents in Gastric Cancer via the Mammalian Target of Rapamycin (mTOR) Signaling Pathway by Interacting with Human Epidermal Growth Factor Receptor 2 (ERBB2).

BACKGROUND In recent years, the incidence of gastric cancer (GC) has been increasing worldwide. Emerging evidence shows that microRNAs (miRs) may be involved in the pathogenesis of GC. Thus, this study explored the mediatory role of miR-495 in GC chemosensitivity, and investigated the mechanism by which it affects the biological behaviors of GC cells via the mTOR signaling pathway. MATERIAL AND METHODS After GC and paracancerous tissue collection, the positive rate of ERBB2 and mTOR was evaluated by immunohistochemistry. Subsequently, the expression of miR-495, ERBB2, and mTOR was determined by RT-qPCR and Western blot analysis. Next, the targeting relationship between miR-495 and ERBB2 was confirmed by dual-luciferase reporter gene assay. In addition, chemosensitivity and proliferation were detected by MTT assay and apoptosis was assessed by flow cytometry. RESULTS We found higher positive rates of ERBB2 and mTOR and decreased expression of miR-495 in GC tissues and showed that ERBB2 is the target gene of miR-495. Furthermore, we determined that overexpression of miR-495 and silencing of ERBB2 enhanced GC cell chemosensitivity and apoptosis, but inhibited GC cell proliferation. We also found that the effect of miR-495 inhibition was lost when ERBB2 was suppressed. CONCLUSIONS The key findings of our study demonstrate that the miR-495 exerts promotive effects on GC chemosensitivity via inactivation of the mTOR signaling pathway by suppressing ERBB2. The study provides reliable evidence supporting the use of miR-495 as a novel potential target in the chemotherapy of GC.

Camrelizumab combined with apatinib for unresectable, metastatic esophageal squamous cell carcinoma: a single-center, single-arm, prospective study.

Background: The prognosis for esophageal cancer (EC), a common malignant tumor, is poor. The new oral small-molecule tyrosine kinase inhibitor apatinib has shown an excellent therapeutic effect on treating EC. Camrelizumab is a humanized programmed death 1 (PD-1) inhibitor with high affinity. Immune checkpoint inhibitors combined with chemotherapy have become the standard first-line treatment for advanced EC. The new combination strategy of anti-angiogenic therapy combined with immunotherapy has great application prospects in the treatment of tumors. We aimed to assess camrelizumab in combination with apatinib as a new combination regimen for advanced or metastatic esophageal squamous cell carcinoma (ESCC). Methods: In this study, we recruited patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, with pathologically confirmed unresectable, locally advanced, locally recurrent, or metastatic ESCC. Each patient received an intravenous infusion of camrelizumab 200 mg and oral administration of apatinib 250 mg once a day, every 21 days, as a cycle until disease progression, intolerance, or death. The primary endpoint was the objective response rate (ORR), while the Kaplan-Meier method and LIFETEST procedure were used to estimate survival functions for overall survival (OS) and progression-free survival (PFS). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used to evaluate adverse events. Results: Between December 1, 2019 and July 31, 2022, 35 patients were enrolled, with 29 patients in the efficacy and safety analysis. The ORR was 34.5%, and the disease control rate (DCR) reached 82.8%. Median OS was 13.8 months (95% CI: 11.2-16.2), and the estimated 6-, 9-, and 12-month OS rates were 85.5% (95% CI: 65.7-94.3%), 80.9% (95% CI: 60.3-91.5%), and 67.0% (95% CI: 43.8-82.4%), respectively. Median PFS was 9.5 months (95% CI: 7.0-13.6). The most prominent grade ≥3 adverse events associated with treatments were alanine aminotransferase (ALT) increase (10.3%), hypertension (10.3%), and reactive cutaneous capillary endothelial proliferation (CCEP) (6.9%), and no deaths occurred due to adverse events. Conclusions: Among patients with advanced or metastatic ESCC, camrelizumab combined with apatinib showed a reasonable remission rate and survival benefit with a manageable safety profile.

Relationship between microRNA-27a and efficacy of neoadjuvant chemotherapy in gastric cancer and its mechanism in gastric cancer cell growth and metastasis.

Objective: The aim of the present study is to investigate the relationship between microRNA-27a (miR-27a) and the efficacy of neoadjuvant chemotherapy in gastric cancer (GC) and its mechanism in the growth and metastasis of GC cells.Methods: The expression of miR-27a in serum of 74 GC patients received neoadjuvant chemotherapy was detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Clinical value and prognosis of miR-27a expression in predicting the efficacy of neoadjuvant chemotherapy in GC were evaluated. Besides, GC cells with low miR-27a expression were transfected with miR-27a mimics, and cells with high miR-27a expression were transfected with miR-27a inhibitors and secreted frizzled-related protein 1 (SFRP1) siRNA. A series of experiments were applied for the determination of cell viability, invasion and migration of GC cells.Results: After neoadjuvant chemotherapy, the expression of miR-27a in serum of GC patients decreased significantly. Additionally, the expression of miR-27a in GC cell line was significantly higher than that in normal gastric mucosa cell line. Meanwhile, after down-regulating the expression of miR-27a in GC cells, the mRNA and protein expression of SFRP1 increased, the proliferation rate of cells slowed down, and the ability of invasion and migration decreased. Furthermore, combined with low expression of miR-27a and SFRP1, the proliferation rate of GC cells increased and the ability of invasion and migration increased.Conclusion: Collectively, our study highlights that the high expression of miR-27a indicates the poor efficacy and prognosis of neoadjuvant chemotherapy in GC patients. Down-regulation of miR-27a can inhibit the growth and metastasis of GC cells via up-regulation of SFRP1.

UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer.

OBJECTIVES: To investigate the relationship between uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1)*28/*6 and toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer (CRC) in Xinjiang Uygur and Han population. METHODS: A total of 183 patients (Uygur, 114; Han, 69) with advanced CRC who received the irinotecan-based chemotherapy were enrolled in this retrospective analysis. Polymerase chain reaction amplification and direct sequencing method were used for UGT1A1*28 and UGT1A1*6 polymorphism detection. The patients were followed up to analyze the relationship between different genotypes with adverse reactions and the clinical outcome of irinotecan-based chemotherapy. RESULTS: Significant differences were found in genotype frequencies of UGT1A1*28 and UGT1A1*28/*6 between Uygur and Han (P = 0.02 and P = 0.002). Uygur and Han patients carrying wild UGT1A1*28 and *6 genotypes appeared to have significantly lower diarrhea incidence (I/II and III/IV) than those carrying mutant genotypes (all P < 0.05). In Uygur patients, UGT1A1*28 genotypes were related with objective response rate and disease control rate (P < 0.05). Compared with *1 allele *1/*1, *1 allele *1/*28*1/*28 mutant of UGT1A1*28 was associated with shorter OS in both Uygur and Han ethnicities (all P < 0.05). Compared with double allele variants (DW), single allele variants (SV), and double allele variants (DV) of UGT1A1*28/*6 were associated with shorter overall survival (OS) in Uygur and Han (all P < 0.05). Cox regression analysis revealed factors significantly influencing OS, including UGT1A1*28, UGT1A1*6, combined genotypes and chemotherapy line in Ugyur, and only combined genotypes in Han (all P < 0.05). CONCLUSION: UGT1A1 gene polymorphism predicts irinotecan-related adverse reactions in advanced CRC patients of Xinjiang Uygur and Han nationality; UGT1A1 gene polymorphism is correlated with efficacy and prognosis in Uygur nationality, but only related to prognosis in Han nationality in irinotecan-based chemotherapy.