Shiyun Cui

This study aims to explore Aurora-A’s role in regulating immune escape of hepatocellular carcinoma (HCC). We performed non-targeted metabolomics analysis and analyzed the impact of Aurora-A inhibitor Alisertib on anti-PD-1 therapy efficacy on xenograft tumors and co-culture models of CD8⁺ T cells and HCC cells. We determined reactive oxygen species (ROS) and malondialdehyde (MDA) production in HCC cells to evaluate lipid peroxidation. Confocal images of endoplasmic reticulum (ER) and mitochondria in HCC cells were taken to assess the role of Aurora-A and dynamin-related protein 1 (Drp-1) on mitochondria-associated endoplasmic reticulum membranes (MAMs) formation. The results showed that Aurora-A was upregulated in HCC cells and its knockdown significantly augmented phosphatidylethanolamine (PE) production while having no effect on phosphatidylserine decarboxylase (PSD). Further, Aurora-A inhibitor Alisertib enhanced the sensibility of HCC cells to anti-PD-1 therapy and CD45⁺CD8⁺ T cell infiltration in HCC tumors. To conclude, our work revealed that Aurora-A dysregulated PS/PE metabolism via facilitating Drp1-Ser616 phosphorylation to disrupt MAMs formation, resulting in suppressed ferroptosis in HCC cells to reduce their sensitivity to anti-PD-1.

Aims: This study investigates the association between circulating tumor cells (CTCs) and breast cancer metastasis. Methods: A retrospective study was conducted using patients with histologically confirmed breast cancer recruited from the First Affiliated Hospital of Nanjing Medical University during the period of August 2017–October 2020. We used adjusted logistic regression, the random forest algorithm, and sensitivity analysis to study the association between CTC enumeration and tumor metastasis. Further, we performed next-generation sequencing (NGS) on the CTCs obtained from two patients with breast cancer brain metastasis. Results: A total of 41 out of 116 enrolled patients were identified with tumor metastasis. CTC enumeration was significantly higher in patients with liver metastasis than in those without liver metastasis. Patients with CTCs ≥ 5 exhibited a higher risk of tumor metastasis than those with CTCs < 5 in the adjusted model (odds ratios (OR) = 6.25, 95% confidence interval (CI) = 2.63–15.58). The random forest model identified CTC enumeration as a significant metastasis-related variable with the highest mean decrease accuracy and mean decrease Gini score. No significant association was found between CTCs and visceral metastasis with an OR of 1.29 (95% CI = 0.98–2.05, p = 0.232). Upon further investigating organ-specific metastasis, we found that patients with high CTC levels were more likely to develop liver metastasis (OR = 4.87, 95% CI = 1.34–20.17, p = 0.021). The NGS study of CTCs identified a total of 120 indel mutations (e.g., CNGB1, NTSR1, ZG16). The enriched biological processes were mechanoreceptor differentiation and macrophage activation involved in the immune response. The enriched KEGG pathways included focal adhesion, the PI3K-Akt signaling pathway, and microRNAs involved in cancer. Conclusions: Our study revealed that CTCs ≥ 5 are a risk factor for tumor metastasis in breast cancer patients. In addition, we reported that CTCs ≥ 5 might be associated with a higher risk of liver metastasis in patients with metastatic breast cancer. We have provided the mutational profiles of CTCs based on next-generation sequencing.

Background. Neurodegenerative diseases, such as Alzheimer’s disease, and traumatic brain and spinal cord injury (SCI) are prevalent in clinical practice. Inhibition of hyperactive inflammation and proliferation of endogenous neural stem cells (NSCs) is a promising treatment strategy for SCI. Our previous studies demonstrated the beneficial effects of rosiglitazone (Rosi) on SCI, but its roles in inflammation inhibition and proliferation of NSCs are unknown. Methods. SCI in a rat model was established, and the effects of Rosi on motor functions were assessed. The effects of Rosi on NSC proliferation and the underlying mechanisms were explored in details. Results. We showed that Rosi ameliorated impairment of moto functions in SCI rats, inhibited inflammation, and promoted proliferation of NSCs in vivo. Rosi increased ATP production through enhancing glycolysis but not oxidative phosphorylation. Rosi reduced mitophagy by downregulating PTEN‐induced putative kinase 1 (PINK1) transcription to promote NSC proliferation, which was effectively reversed by an overexpression of PINK1 in vitro. Through KEGG analysis and experimental validations, we discovered that Rosi reduced the expression of forkhead box protein O1 (FOXO1) which was a critical transcription factor of PINK1. Three FOXO1 consensus sequences (FCSs) were found in the first intron of the PINK1 gene, which could be potentially binding to FOXO1. The proximal FCS (chr 5: 156680169–156680185) from the translation start site exerted a more significant influence on PINK1 transcription than the other two FCSs. The overexpression of FOXO1 entirely relieved the inhibition of PINK1 transcription in the presence of Rosi. Conclusions. Besides inflammation inhibition, Rosi suppressed mitophagy by reducing FOXO1 to decrease the transcription of PINK1, which played a pivotal role in accelerating the NSC proliferation.

Introduction: Deleterious heterozygous mutation of the MLH1 gene is an important cause of Lynch syndrome (LS), an autosomal dominant cancer caused by functional defects in the DNA mismatch repair (MMR) complex. Case Report: The proband was a 35-year-old patient with confirmed colorectal cancer (CRC). Immunohistochemical (IHC) staining revealed the absence of MLH1 and PMS2 expression in the colorectal tissue specimens of the patient. Genetic counselling and tumor gene testing were performed using next-generation sequencing technology. The genetic tumor verification report showed the deletion of 4 bases in exon 12 of the tested MLH1 gene and a transcoding mutation. To our knowledge, this germline splice site mutation of MLH1 has not been reported before. The proband accepted several therapeutic regimens including PD-1 inhibitor and ultimately died of multiple organ failure. Conclusion: Nonsense mutations and frameshift mutations of MMR genes are the most common causes of LS. Common mutations include those in MSH2, MLH1, MSH6, and PMS2. We report a mutation of MLH1 that has never been reported before. We recommend that patients with a history of colon or rectal cancer receive universal MMR or MSI testing and checkpoint inhibitor therapy for the first-line treatment of deficient MMR CRC.

As a very promising immunotherapy, PD-1/PD-L1 blockade has revolutionized the treatment of a variety of tumor types, resulting in significant clinical efficacy and lasting responses. However, these therapies do not work for a large proportion of patients initially, which is called primary resistance. And more frustrating is that most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms that lead to primary and acquired resistance to PD-1/PD-L1 inhibition have remained largely unclear. Recently, the gut microbiome has emerged as a potential regulator for PD-1/PD-L1 blockade. This review elaborates on the current understanding of the mechanisms in terms of PD-1 related signaling pathways and necessary factors. Moreover, this review discusses new strategies to increase the efficacy of immunotherapy from the perspectives of immune markers and gut microbiome.

Hepatocellular carcinoma (HCC) is the sixth most deadly malignant cancer in the world and has the third highest mortality rate among cancer-related deaths worldwide. Its poor prognosis can be attributed to late diagnosis, high risk of recurrence and drug resistance. Therefore, finding a new biomarker to help us in the early diagnosis, and exploring the molecular mechanisms involved in recurrence and drug resistance is a reasonable research direction for clinical treatment of HCC. At present, the exosomes related to HCC have been confirmed to carry ncRNAs, transfer them to target cells, and bind corresponding target molecules. Furthermore, they affect the proliferation and metastasis of hepatocellular carcinoma by promoting angiogenesis, epithelial-mesenchymal transition (EMT), and inhibiting the function of the body's immune system. They play an important role in the recurrence and resistance of HCC. Besides, exosomes are stably expressed in body fluids such as sera, are easy to collect and cause little harm to the human body. They are the best candidates for liquid biopsy. Therefore, exosomal ncRNAs have application prospects as biomarkers and targeted molecules for therapy. This article summarizes the current research involving ncRNAs in HCC-related exosomes.

染色体外DNA（extrachromosomal DNA, ecDNA）是位于染色体外的小片段环状DNA，具有自我复制功能。已有研究证明癌基因在ecDNA上被扩增是肿瘤细胞中的常见现象，并且具有一些值得研究的特征，如与患者的不良预后相关。多种染色体事件参与ecDNA形成，且它的扩增能直接使染色体外癌基因DNA拷贝数增加，加速肿瘤产生和发展。并且，亲代ecDNA细胞不均等传递到子代的分离方式，不仅增加肿瘤异质性，同时增强肿瘤对环境的适应和对治疗的反应能力。本文对ecDNA在肿瘤细胞中的研究现状及其潜在意义作一综述。

Long noncoding RNAs (lncRNA) have been found to play critical roles in tumorigenesis and the development of various cancers, including hepatocellular carcinoma (HCC). Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) has been identified as an oncogene and prognostic biomarker in HCC. Here, we demonstrated that MALAT1 expression was obviously high in sorafenib-resistant HCC cells. Furthermore, knockdown of MALAT1 increased sorafenib sensitivity in nonresponsive HCC cells, whereas forced expression of MALAT1 conferred sorafenib resistance to responsive HCC cells in vitro. In addition, loss/gain-of-function assays revealed that MALAT1 promoted cell proliferation, migration, and epithelial–mesenchymal transition in HCC cells. Mechanistically, MALAT1 regulated Aurora-A expression by sponging miR-140-5p, thus promoting sorafenib resistance in HCC cells. Moreover, MALAT1 inhibition enhanced the antitumor efficacy of sorafenib in vivo. Clinically, we found that MALAT1 expression was negatively correlated with miR-140-5p expression but positively correlated with Aurora-A expression in patients with HCC and that upregulated MALAT1 was closely correlated with poor survival outcomes in patients with HCC. These findings indicated that MALAT1 may be a novel target for prognosis prediction and therapeutic strategies in patients with HCC treated with sorafenib.

Pancreatic cancer is associated with a very poor prognosis highlighted by the close association between the disease incidence and mortality. Pancreatic cancer commonly metastasizes to the liver, peripancreas, common bile duct, stomach, duodenum, and retroperitoneum. Conversely, rectal metastasis from pancreatic cancer is extremely rare. We report a rare case of a 75-year-old man with rectal metastasis from a primary pancreatic carcinoma resected 2 years prior. The patient underwent radiotherapy and chemotherapy, but the patient died of increased tumor load. Our understanding of pancreatic cancer has advanced dramatically in the past decade. Distant metastasis should be taken into account when a patient has a medical history of pancreatic adenocarcinoma, even when a rare metastasis site is involved. Histopathological characteristics and immunohistochemical tests are helpful for diagnosis.

The molecular mechanism responsible forHelicobacter pyloriinfection-mediated gastritis and carcinogenesis is not yet clear. Increased evidence suggests that chronic gastritis and elevated gastric epithelial cell (GEC) apoptosis are crucial events during stomach carcinoma transformation. PUMA is a potent proapoptotic Bcl-2 protein and mediates acute tissue injury. In this study, we aimed to investigate the role of PUMA in GEC apoptosis and inflammation induced byH. pyloriinfection. As a result, we found that PUMA expression was elevated in gastritis tissues compared with uninvolved tissues, and it was correlated with the severity of apoptosis and gastritis. In mice,PUMAmRNA and protein were markedly induced in GECs upon induction of gastritis byH. pylori.PUMA-deficient mice were highly resistant to apoptosis and gastritis induced byH. pylori. Furthermore, the transcription factor NF-κB p65 binds toPUMApromoter to activatePUMAtranscription afterH. pyloriinfection. In addition, NF-κB inhibitor could rescueH. pylori-induced apoptosis and gastritis. Finally,H. pylori-induced activation ofp-p65andPUMAwas mediated via Toll-like receptor 2 (TLR2) and blocked inTLR2knockout mice. Taken together, these results verified the pro-inflammatory effect of PUMA inH. pylori-infected gastric tissue. Moreover, TLR2/NF-κB-mediated transcriptional regulation ofPUMAcontributes to the pathogenesis ofH. pylori-infected gastritis.