Chinese Clinical Oncology

In vitro study on the inhibitory effect of antibody coupled drug Disitamab Vedotin on gastric cancer cells with different expression levels of HER-2

JIN Yangbing, CAI Qu, JI Jun, SHI Min, ZHANG Jun.

Chinese Clinical Oncology. 2023, 28 (01): 1-7.

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Objective To evaluate the antitumor activity and the potential beneficiaries of HER-2 antibody drug conjugate (Disitamab Vedotin，RC48) in gastric cancer cells with different HER-2 expression levels. Methods Human NCI-N87, MKN45, MKN7, HGC27, MGC803 gastric cancer cell lines were detected by real time fluorescent quatitative PCR(qRT-PCR), Western blotting combined with confocal cell immunofluorescence to expose their expression and cellular localization of HER-2 in gastric cancer. Subsequently, the above cell lines were treated with different concentrations of RC48 to detect lethal effect and evaluate half inhibitory concentration(IC₅₀) by using cell counting kit (CCK)-8 assay in vitro gastric cancer models. In addition, qRT-PCR and Western blotting techniques were performed to detect the HER-2 mRNA and protein expression level of different gastric cancer cell lines after exposed to RC48. Results Among the gastric cancer cell lines tested, NCIN87 cells had the highest expression of HER-2, while the rest of the cell lines showed weak HER-2 expression. The immunofluorescence confocal showed that HER-2 was mainly located in the cell membrane. RC48 had a dose and timedependent inhibitory effect on HER-2 strongly positive gastric cancer cells (NCI-N87), with IC₅₀ of 48 h and 72 h showed 0.32 μg/ml and 2.359e^-010 μg/ml, respectively. At the same time, it also showed certain antitumor effect in HER-2 low expression cell models like MKN45, MKN7, HGC27, MGC803, with IC50 of 48 h showed 331.90, 24.20, 35.32 and 9.449 μg/ml, respectively. Regardless of the level of HER-2 protein expression at baseline, the expression of HER-2 in gastric cancer cells after RC48 treatment was significantly decreased. Conclusion RC48 can inhibit the proliferation of different gastric cells with different expression levels of HER-2 in a certain time and dose-manner. At the same time, RC48 can also inhibit the expression of HER-2 protein in gastric cancer cells, which efficacy does not completely depend on the level of baseline HER-2 expression.

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Effects of CST1 on proliferation, migration and invasion of non-small cell lung cancer cells via Notch signaling pathway

LIU Yu, YANG Huaqing, ZHAO Bin, DU Li.

Chinese Clinical Oncology. 2023, 28 (01): 8-15.

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Objective To explore the potential mechanism by which Cystatin SN (CST1) affects the proliferation, migration and invasion of non-small cell lung cancer (NSCLC) cells via Notch signaling pathway. MethodsGEPIA was used to analyze the CST1 level in NSCLC tissues from The Cancer Genome Atlas (TCGA) database. Levels of CST1 in NSCLC cells were determined by real time-quantitative polymerase chain reaction (qPCR). Effects of CST1 on the biological behavior of A549 cells was evaluated by transfecting the small interfering RNA sequence si-CST targeting CST1 into A549 cells. Subsequently, Notch pathway activator (VPA-d4) was given on the basis of transfection with si-CST to evaluate the effect of CST1 regulating Notch signaling pathway on the biological behavior of A549 cells. Notch pathway inhibitor (IMR-1) was given alone to verify the promotion of Notch signaling pathway on the biological behavior of A549 cells. CCK-8, scratch assay and Transwell chamber assay were conducted to evaluate the cell proliferation, migration and invasion abilities. Moreover, qPCR and Western blotting were used to detect the levels of Notch1, hairy and enhancer of split 1 (Hes1) and matrix metallopeptidase-9 (MMP9). Results CST1 were up-regulated in NSCLC tissues (P<0.05). Levels of CST1 in NSCLC cells including H1299, H460, H1975, SPC-A1, H1650 and A549 were increased compared with BEAS-2B cell (P<0.05). A549 cells treated with si-CST or IMR-1 had lower proliferative activity, scratch healing rate and number of penetrating membranes than control cells as accompanied by down-regulated Notch1 and Hes1 (P<0.05). A549 cells treated with si-CST plus VPA-d4 had higher proliferative activity, scratch healing rate and number of penetrating membrane than cells treated with si-CST alone as accompanied by up-regulated Notch1, Hes1 and MMP-9 (P<0.05). ConclusionCST1 is up-regulated in NSCLC tissues and cells and may play a role in promoting cancer in NSCLC by activating Notch signaling pathway. It is expected to become a new biomarker and potential therapeutic target for NSCLC treatment.

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Correlation of acetyltransferase KAT2A and survivin protein acetylation in esophageal cancer

LIANG Zongying, ZHAO Baoshan, ZHENG Jingxiong, HOU Jishen, SUN Guangrui.

Chinese Clinical Oncology. 2023, 28 (01): 16-22.

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Objective To investigate the expression of acetyltransferase 2A (KAT2A) and survivin protein acetylation levels in esophageal cancer tissue, and to analyze the correlation and clinical significance during the onset of esophageal cancer. Methods Seventy cases of esophageal squamous carcinoma tissues and adjacent cancer tissues were collected. The survivin and KAT2A mRNA expression was determined by reverse transcription and real-time PCR(qRT-PCR), the expression levels of survivin and KAT2A protein were detected by Immunohistochemistry and Western blotting. Fluorescence immunohistochemistry (IF) verified the location and expression of survivin and KAT2A in cancerous tissues.The survivin protein acetylation was detected by co-immunoprecipitation. The correlation between survivin protein acetylation and KAT2A, and the relationship between them and the clinicopathological characteristics of esophageal cancer were analyzed. KAT2A RNA interference sequences was constructed, then transfected into EC109 cells using liposome-mediated methods. qRT-PCR and Westrern blotting were used to detect the expression level of KAT2A mRNA and protein in esophageal cancer EC109 cells transfected with siRNA-KAT2A. The acetylation level of survivin protein was detected by co-immunoprecipitation. Results The relative expression of survivin and KAT2A mRNA was higher in esophageal cancer tissues than that in adjacent cancer tissues（P＜0.05）. Survivin and KAT2A protein were highly expressed in esophageal cancer tissues, whereas low expressed in adjacent cancer tissues. The survivin protein was acetylated in esophageal cancer tissues. Immunofluorescence confirmed that survivin and KAT2A protein both show a high expression state in cancer tissues, which are mainly expressed in the cytoplasm, partially expressed in the nucleus, and the acetylation rate was significantly higher than that in adjacent cancer tissues（P＜0.05）. Survivin acetylation and KAT2A were related in esophageal cancer tissues, and it was positive correlation（r=0.517, P＜0.05）. Survivin protein acetylation and KAT2A are closely related to tumor TNM staging, differentiation grade and lymph node metastasis（P＜0.05）. The result of vitro experiments showed that there was no change in survivin mRNA and protein expression after downregulation of KAT2A by RNA interference（P＞0.05）, but the acetylation level of survivin protein was significantly reduced（P＜0.05）. Conclusion Acetyltransferase KAT2A is involved in the survivin acetylation modification during the esophageal lesion. High expression of KAT2A may be an important molecular event of survivin acetylation modification and has potential value in the diagnosis and treatment of esophageal cancer.

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Expression of S100A16 in esophageal squamous cell carcinoma and the effects on the migration and invasion of esophageal carcinoma cells

WANG Hai, ZHAO Cuiping, ZHOU Linyan, KAN Jingbao, SHI Yongkang, ZHA Quanbin.

Chinese Clinical Oncology. 2023, 28 (01): 23-29.

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Expression of S100A16 in esophageal squamous cell carcinoma and the effects on the migration and invasion of esophageal carcinoma cells

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Construction and validation of prognostic nomogram for malignant meningioma based on SEER database

QIU Sichong, XU Luyu, LI Liuning

Chinese Clinical Oncology. 2023, 28 (01): 30-37.

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Objective To construct and validate a nomogram model for the prognosis of malignant meningioma based on SEER database. Methods The clinical data of patients with malignant meningioma from 1992 to 2019 were obtained from SEER database by SEER*Stat 8.4.0 software, and the screened cases were randomly divided into training set and validation set in a ratio of 8∶2. Using R 4.1.3 software, Lasso regression and multivariate Cox regression analysis were used to determine the independent prognostic factors of malignant meningioma, and the nomogram model of 1-year, 3-year and 5-year overall survival was constructed. The reliability of the nomogram was assessed by C-index, receiver operating characteristic curve (ROC), calibration curve and the risk stratification analysis. Results A total of 717 patients were screened, including 576 in the training set and 141 in the validation set. After Lasso regression and multivariate Cox regression, age, gender, marital status and surgery were determined as independent prognostic factors for malignant meningioma（P＜0.05）. The C-index of the training set and validation set were 0.683 and 0.681, respectively. For the area under the curve (AUC) values of 1-year, 3-year and 5-year overall survival, the training set was 0.738, 0.717 and 0.747, the validation set was 0.704, 0.664 and 0.700. The calibration curve of the model showed that the predicted survival probability derived from the nomogram was in good agreement with the actual observed value. In addition, decision curve analysis (DCA) also showed that the nomogram had better benefit. After risk stratification of patients with malignant meningioma according to prognostic factors, there was a significant difference in the overall survival between the high and low risk groups (P<0.001). Conclusion Age, gender, marital status and surgery are related to the prognosis of patients with malignant meningioma. The nomogram model constructed in this study can more accurately predict the prognosis of patients with malignant meningioma, but its wide application still needs external and prospective verify.

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Establishment of prognostic risk evaluation model for gastric cancer integrating ferroptosis and immune-related genes

ZHANG Yujun, WANG Yan, ZHU Lin, CAI Yingbin

Chinese Clinical Oncology. 2023, 28 (01): 38-48.

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Objective To explore the prognostic value of ferroptosis related genes (FRGs) and immune related genes (IRGs) in gastric cancer and build a prognostic risk model to predict the overall survival (OS). MethodsThe transcriptome data and clinical data of gastric cancer were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and FRGs and IRGs were extracted from FerrDb and Immport databases. The TCGA expression profile genes were intersected with FRGs and IRGs to obtain gastric cancer FRGs and IRGs. The differential FRGs and IRGs with prognostic value were screened by differential analysis and prognostic correlation analysis, and the intersection was obtained by Venn plot. The ferroptosis death related gene risk score (FRG risk-score) and immune related gene risk score (IRG risk-score) models were further screened by LASSO-Cox regression. FRG riskscore and IRG risk-score models were evaluated by Kaplan-Meier survival analysis, receiver operating characteristic curve (ROC), principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), univariate and multivariate Cox regression analysis, and nomograms and calibration curves combining clinicopathological features, FRG riskscore and IRG riskscore were constructed. Meanwhile, the GSE84437 dataset was used to validate the model. Cibersort algorithm was used to estimate the abundance of 22 kinds of infiltrating immune cells in all samples of TCGA cohort and the correlation between FRGs, IRGs and immune cell infiltration was analyzed using TIMER database. TCIA and TIDE websites were used to analyze the difference of immune drug sensitivity and immune escape score between different risk groups. ResultsA total of 8 overlapping candidate FRGs and 4 overlapping candidate IRGs were obtained through screening. LASSO-Cox regression results showed that five FRGs (ZFP36, NOX4, SLC1A5, MYB, DUSP1) and four IRGs (CGB5, GHR, GLP2R, NPR1) were included in the prognostic model. Kaplan-Meier survival analysis, area under ROC curve (AUC), PCA and tSNE analysis all verified that the model had good prediction ability. Combining the clinicopathological features, nomograms of FRG risk-score and IRG risk-score and their calibration curves, it is shown that the model has a good predictive ability for 1-year and 3-year survival rates of gastric cancer patients. The results of correlation analysis between immune cell infiltration and model genes showed that there was a significant correlation between FRGs and IRGs and the level of immune cell infiltration (P<0.05). Immunopharmacotherapy analysis showed that patients in the low-risk group with FRGs prognostic characteristics had better immunotherapeutic response to CTLA4 blockers. Immune escape results showed that patients in the high-risk group of FRGs and IRGs prognostic models had higher TIDE scores. Conclusion The prognosis model integrating FRGs and IRGs can better predict the prognosis of gastric cancer patients, and can be used as an early detection biomarker and an anti-tumor immunotherapy target, which has clinical therapeutic significance.

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Clinical prognostic value and molecular mechanism of UBE2C gene in kidney renal clear cell carcinoma

ZHAN Tianpeng, HE Wei, ZHANG Meng, TAO Yan, LU Jianzhong, FU Shengjun, LI Lanlan, ZHANG Jing, LIU Shanhui

Chinese Clinical Oncology. 2023, 28 (01): 49-57.

Abstract ( 206 )

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Objective To explore the expression pattern, clinical prognostic value and molecular mechanism of ubiquitin-conjugating enzyme E2C(UBE2C) in kidney renal clear cell carcinoma(KIRC). Methods The difference of UBE2C gene expression in KIRC tissue and normal tissue was analyzed by The Cancer Genome Atlas(TCGA) and Human Protein Atlas(HPA). Combined with clinical information of KIRC patients, univariate and multivariate Cox regression analysis models were used to study the prognostic value of UBE2C gene in KIRC patients. Through gene set enrichment analysis(GSEA) of UBE2C gene, we understood the molecular mechanism of UBE2C regulating KIRC. The infiltrating immune cells content in KIRC patients were calculated, and the correlation between UBE2C gene expression level and immune cells infiltration content were evaluated. ResultsBoth gene and protein expression levels of UBE2C in KIRC tissues were higher than those in normal tissues (P<0.05). The expression of UBE2C in KIRC was correlated with tumor location, histological grade, pathological stage and TNM stage(P<0.05). Univariate and multivariate Cox regression analysis cleared that UBE2C was an independent prognostic factor for KIRC(P<0.05). GSEA results suggested that UBE2C could be involved in the regulation of cytokinecytokine receptor interactions, cell cycle checkpoints, ECM glycoproteins and other signaling pathways. The expression level of UBE2C gene was significantly correlated with the infiltration of Treg cells, T cells, Th17 cells, B cells, CD8+T cells and macrophages in the tumor microenvironment of KIRC. UBE2C was also significantly correlated with the expression levels of immune checkpoint molecules PDCD1 (PD1), CTLA4, CD27 and LAG3. Conclusion UBE2C can serve as a risk prognostic factor for KIRC patients, and UBE2C may be a potential target for KIRC treatment.

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Clinicopathological analysis of 5 cases of primary MALT lymphoma of salivary gland

YANG Jiajia, HUANG Caihong, JIANG Shuwan, WANG Zheng, DING Zhiyan.

Chinese Clinical Oncology. 2023, 28 (01): 58-63.

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Objective To investigate the clinicopathological features of mucosa associated lymphoid tissue (MALT ) lymphoma in the extranodal margin of salivary gland. Methods The clinicopathological data of 5 cases of salivary gland MALT lymphoma were analyzed retrospectively, and the relevant literature was reviewed. ResultsThere were 3 females and 2 males. The age of onset ranged from 32 to 71 years. The mass was located in unilateral parotid gland/submandibular gland. Tumor cells are mainly composed of B cells in various forms of tumor marginal area, with diffuse or nodular infiltration and growth. “follicular implantation”, “lymphoepithelial lesions” with intraductal aggregation and growth, increased basement membrane like eosinophils around ductal epithelium, and vascular and nerve invasion could be found. Tumor cells were diffusely positive for B cell related antigen, negative for CD5, CD23 and CyclinD1, and Ki-67 index was 10%-30%. During the follow-up of 8 to 97 months, 5 cases had no radiotherapy or chemotherapy, 3 cases had no recurrence, 1 case had secondary MALT lymphoma of the right upper palate, and 1 case died. Conclusion Salivary gland MALT lymphoma has certain morphological characteristics, showing B cell immunophenotype and no other phenotypic characteristics of small B cell lymphoma. The disease shows an inert process, and the prognosis is generally good. It can involve the surrounding lymph nodes and other salivary glands. There is a risk of recurrence and distant spread, which requires long-term close follow-up.

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Clinicopathological features of 9 cases of synchronous endometrial and ovarian cancer

LI Li, WU Jinrong, HAN Mei, KE Fei, LI Xiuqing, ZHANG Yifen.

Chinese Clinical Oncology. 2023, 28 (01): 64-69.

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Objective To investigate the clinicopathological features of synchronous endometrial and ovarian cancer (SEOC). Methods The clinicopathological data of 9 cases of pathologically proven SEOC from August 2009 to August 2020 were analyzed retrospectively. The clinicopathological features were discussed and related literatures were reviewed. ResultsAll patients aged from 29 to 65 years with a mean of 47.44 years old, and the first symptoms were mainly abnormal uterine bleeding. All of the endometrial cancers were low grade endometrioid carcinomas, and mainly FIGO Grade 1 (G₁), stageⅠ. Eight patients were accompanied by endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN). As to ovarian cancers, 8 were low grade endometrioid carcinomas (G₁ and G₂) and 1 was clear cell carcinoma. All were stageⅠcancers. Most were unilateral ovarian involvement, and 6 patients accompanied by ovarian endometriosis. All patients had no lymphatic vessel space invasion (LVSI) or fallopian tube involvement. Four patients underwent ascites cytology, only 1 case was found positive peritoneal cytology. Mismatch repair (MMR) deficiency was found in two patients. In Case 5, the patient had a history of colon adenocarcinoma and the expression of MLH1 and PMS2 was lost in endometrial cancer, ovarian cancer and colon adenocarcinoma immunohistochemistry. In Case 8, the pathological type of ovarian cancer was clear cell carcinoma and the expression of MSH2 and MSH6 was lost in endometrial and ovarian cancer immunohistochemistry. All patients received surgical treatment and postoperative adjuvant therapy. Conclusion SEOC usually occurs in young women. The histological type was low grade endometrioid carcinoma and low pathological stage. Surgical resection was the main treatment, and the prognosis was good.

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Advances in the prevention and treatment of cardiotoxicity caused by anti-tumor drugs

TAI Xiaohui, ZHANG Lingfang, DANG Chunyan, ZHANG Xuxia, XUE Li, LIU Le, LI Hongling.

Chinese Clinical Oncology. 2023, 28 (01): 70-76.

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With the improvement in the treatment of malignant tumors, anti-tumor drugs such as chemotherapy, targeted therapy, endocrine therapy and biological immune agents related to heart damage have become a challenge for long-term survival of cancer patients，seriously affecting the quality of life of patients. In some tumor populations, the long-term risk of cardiovascular death has exceeded the risk of cancer death. To reduce the risk of cardiovascular disease, there is increasing emphasis on the use of cardioprotective strategies at the start of anti-tumor treatment. Relevant studies have shown that dexamethasone, neurohormone antagonists, adenosine phosphate-activated protein kinase (AMPK) activators can interfere with cardiac injury related to anti-tumor therapy. Evidence from recently completed and ongoing clinical trials of antineoplastic drugs for the prevention and treatment of cardiotoxicity is reviewed.

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Current status and prospect of immune checkpoint inhibitors in treatment of advanced soft tissue sarcoma

XUE Luxin, ZHANG Zhifan, LIU Fangcen, WANG Xiaolu, WANG Qin, LIU Baorui, LI Rutian.

Chinese Clinical Oncology. 2023, 28 (01): 77-83.

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Soft tissue sarcomas (STS) are a rare group of mesenchymal malignancies except bone or cartilage, with a low incidence rate. Patients with advanced STS have limited treatment options, poor prognosis and high mortality. Recently, immune checkpoint inhibitors (ICIs) have made great breakthroughs in the field of tumor therapy, greatly improving the prognosis of patients with various malignancies. However, efficacy of ICIs in the treatment of STS remains unravelled. This review summarizes the role of the ICIs in various sets of advanced STS treatment and provides future research directions, hoping to serve as a reference for clinicians.

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Advances in treatment of peritoneal metastasis from colorectal cancer

XU Lu, SUN Jing.

Chinese Clinical Oncology. 2023, 28 (01): 84-89.

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Colorectal cancer is the third most common cancer in the world and the fourth most common cause of cancer-related death. Metastatic diseases are still the main cause of colorectal cancer death. Except lymphatic and blood transmission routes, colorectal cancer will also cause the intraperitoneal transmission of tumor cells and eventually lead to peritoneal cancer. With the progress of various treatments, the prognosis of patients with metastatic colorectal cancer has improved significantly, but the curative effect on patients with peritoneal metastasis is not ideal. Recently, more and more evidence shows that patients with colorectal cancer with peritoneal metastasis can benefit from cytoreductive surgery (CRS) and hot intraperitoneal chemotherapy (HIPEC), and have a good prognosis. New therapies such as pressurized intraperitoneal aerosol chemotherapy (PIPAC), neoadjuvant chemotherapy, and Radspherin short distance radiation also appear. This article reviews the research progress of colorectal cancer with peritoneal metastasis.

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Prevalence and prevention strategies of cervical cancer in the world and China

CAI Huilong, YUAN Weiguang, SUN Huixin.

Chinese Clinical Oncology. 2023, 28 (01): 90-93.

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The International Agency for Research on Cancer (IARC) estimates 36 cancer incidence rate and mortality rates in 185 countries/regions through GLOBOCAN 2020 database. Globocan2020 database shows that cervical cancer is the fourth largest tumor in women in the world, whether it is morbidity or mortality. The harm of cervical cancer to women's health and its prevention and treatment are important public health issues facing the world. This paper will summarize and compare the incidence and death prevalence of cervical cancer in the world and China from the aspects of population characteristics, regional distribution and time change trend, and combined with the reported human papillomavirus and other risk factors, primary prevention and secondary prevention strategies of cervical cancer, in order to provide scientific clues for the prevention and treatment strategies of cervical cancer in the future.

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标准刊号：	ISSN 1009-0460
	CN 32-1577/R