Targeting EFNA1 suppresses tumor progression via the cMYC-modulated cell cycle and autophagy in esophageal squamous cell carcinoma.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) remains one of the most common causes of cancer death due to the lack of effective therapeutic options. New targets and the targeted drugs are required to be identified and developed. METHODS: Highly expressed genes in ESCA were identified using the edgeR package from public datasets. Immunostaining assay verified the high expression level of EFNA1 in ESCC. CCK-8, colony formation and wound healing assays were performed to examine the role of EFNA1 and EPHA2 in ESCC progression. Cell cycle was analyzed by flow cytometry and autophagy activation was determined by autophagolysosome formation using transmission electron microscopy. The small molecule targeting to EFNA1 was identified by molecular docking and the anti-tumor effects were verified by in vitro and in vivo models with radiation treatment. RESULTS: EFNA1 was highly expressed in esophageal cancer and significantly associated with poor prognosis. Downregulation of EFNA1 remarkably inhibited cell proliferation and migration. Furthermore, decreased EFNA1 significantly suppressed the expression of cMYC along with its representative downstream genes involved in cell cycle, and activated autophagy. Similar effects on ESCC progression were obtained from knockdown of the corresponding receptor, EPHA2. The potential small molecule targeting to EFNA1, salvianolic acid A (SAA), could significantly suppress ESCC progression and increase the sensitivity to radiotherapy. CONCLUSION: We revealed that EFNA1 facilitated the ESCC progression via the possible mechanism of activating cMYC-modulated cell proliferation and suppressing autophagy, and identified SAA as a potential drug targeting EFNA1, providing new options for the future treatments for ESCC patients.

Long Noncoding RNA KLF3-AS1 Acts as an Endogenous RNA of miR-223 to Attenuate Gastric Cancer Progression and Chemoresistance.

Gastric cancer is a deadly disease, and the low rate of early diagnosis and chemoresistance largely contributed to the poor prognosis of gastric cancer. LncRNAs have been extensively reported for their roles in regulating cancer progression. In this study, we found that KLF3-AS1 was down-regulated in gastric cancer cells. Overexpression of KLF3-AS1 repressed gastric cancer cell proliferation, growth. In addition, KLF3-AS1 overexpression also exerted inhibitory effects on the gastric cancer cell invasion, migration and EMT, but promoted chemosensitivity of gastric cancer cells to cisplatin. The mechanistic studies showed that KLF3-AS1 could act as the "sponge" for miR-223 and to repress miR-223 expression in gastric cancer cells. Overexpression of miR-223 reversed the inhibitory effects of KLF3-AS1 overexpression on gastric cancer cell proliferation, invasion, migration and EMT, and attenuated the enhanced effects of KLF3-AS1 overexpression on gastric cancer cell chemosensitivity to cisplatin. The in vivo studies showed that KLF3-AS1 overexpression suppressed the tumor growth of SGC-7901 in the nude mice. In conclusion, our results for the first time demonstrated that KLF3-AS1 was down-regulated in gastric cancer cells and repressed gastric cancer cell proliferation, invasion, migration and EMT, and enhanced chemosensitivity to cisplatin. Further mechanistic results indicated that KLF3-AS1 exerted its biological function in gastric cancer cells by inhibiting miR-223 expression. Future studies are still required to decipher the detailed molecular mechanisms of KLF3-AS1 in gastric cancer.

Corrigendum: Metagenome Analysis of Intestinal Bacteria in Healthy People, Patients With Inflammatory Bowel Disease and Colorectal Cancer.

[This corrects the article DOI: 10.3389/fcimb.2021.599734.].

Vitamin D suppressed gastric cancer cell growth through downregulating CD44 expression in vitro and in vivo.

OBJECTIVES: Vitamin D deficiency was found to be associated with increased risk for gastric cancer (GC). We previously found that vitamin D inhibited GC cell growth in vitro. However, the in vivo antitumor effect of vitamin D in GC as well as the underlying mechanisms are not well understood. The aim of this study was to investigate the anticancer effect of vitamin D on GC both in vitro and in vivo. METHODS: Human GC cells MKN45, MKN28, and KATO III were used. The expressions of vitamin D receptor (VDR) and CD44 were downregulated by using predesigned siRNA molecules. Cell viability was evaluated by methyl thiazolyl tetrazolium assay. Soft agar assay was used for colony formation of GC cells. Flow cytometry was used to assess CD44-positive cell population. CD44high cancer cells were enriched by using anti-CD44-conjugated magnetic microbeads. Quantitative real-time polymerase chain reaction and Western blot were performed to detect gene and protein expressions, respectively. Clinical samples were collected for evaluation of the correlation of VDR and CD44 expression. Orthotopic tumor-bearing mice were established to evaluate the antitumor effect of vitamin D. RESULTS: The results showed that the active form of vitamin D, 1,25(OH)2D3, had a remarkable inhibitory effect in CD44-expressing human GC MKN45 and KATO III cells, but not in CD44-null MKN28 cells. The gene expressions of CD44 and VDR in GC cell lines and GC patient tissues were positively correlated. Furthermore, 1,25(OH)2D3 suppressed MKN45 and KATO III cell growth through VDR-induced suppression of CD44. Additionally, we demonstrated that 1,25(OH)2D3 inhibited Wnt/ß-catenin signaling pathway, which might lead to the downregulation of CD44. In an orthotopic GC nude mice model, both oral intake of vitamin D and intraperitoneal injection with 1,25(OH)2D3 could significantly inhibit orthotopic GC growth and CD44 expression in vivo. CONCLUSION: To our knowledge, this study provided the first evidence that vitamin D suppressed GC cell growth both in vitro and in vivo through downregulating CD44. The present study sheds light on repurposing vitamin D as a potential therapeutic agent for GC prevention and treatment.

MiRNA-339 targets and regulates ZNF689 to inhibit the proliferation and invasion of gastric cancer cells.

BACKGROUND: Gastric cancer (GC) is the most common malignant tumor of the digestive system, and its mortality rate ranks first among malignant tumors. However, the pathogenesis of GC has not yet been fully elucidated. This study found that microRNA (miRNA)-339 is abnormally expressed in GC tissues. However, the role and molecular mechanism of miRNA-339 in the occurrence and development of GC are still unclear. METHODS: Fluorescence quantitative polymerase chain reaction (qPCR) was used to detect the expression level of miRNA-339 in GC tissues and adjacent tissues and analyze the correlation with the clinicopathological characteristics of GC patients. Cell counting kit-8 (CCK-8) and Transwell experiments detected the effect of overexpression of miRNA-339 on the proliferation, invasion, and migration of GC cells. The luciferase reporter gene detected the downstream target molecules regulated by miRNA-339, and western blot was employed to detect the effect of overexpression of miRNA-339 on the expression of ZNF689. RESULTS: The results of fluorescence qPCR showed that miRNA-339 was less expressed in GC tissues compared with adjacent tissues, and it was correlated with the patient's clinical tumor, node, metastasis (TNM) grade and lymph node metastasis. Cell function experiments showed that overexpression of miRNA-339 can significantly inhibit the proliferation, invasion, and migration of GC cells. The luciferase reporter gene showed that miRNA-339 can bind to the 3'-UTR region of ZNF689, and overexpression of miRNA-339 can significantly inhibit the expression of ZNF689 in GC cells. Overexpression of ZNF689 can significantly block the ability of overexpression of miRNA-339 to inhibit the proliferation and migration of GC cells. CONCLUSIONS: miRNA-339 inhibits the proliferation and invasion of GC cells through targeted regulation of the expression of ZNF689. In addition, the expression level of miRNA-339 can be used as a biomarker for the prognosis of GC.

[Diagnosis and treatment of mesenteric venous thrombosis early after operation].

OBJECTIVE: To analyze the clinical characteristics diagnosis and treatment of patients with mesenteric venous thrombosis early after operation. METHODS: A retrospective study was performed on the clinical data of 7 patients with mesenteric venous thrombosis early after operation from 1990 to 2004. RESULTS: Patients had main clinical manifestations of severe abdominal pain and vomiting, but abdominal signs were slight. The systemic toxic symptoms occurred in 2 cases at late course. The examination of abdominal X- ray showed intestinal obstruction of all patients. Four patients received abdominal CT- scanning, of whom 3 patients were diagnosed as mesenteric venous thrombosis. Seven patients received exploratory operation. The necrotic intestinal segments were resected. Two patients had short intestinal syndromes after operation, one of them died of serious malnutrition. Four patients who had recurrence of portal, mesenteric and iliac venous thrombosis needed a long-term therapy of warfarin and aspirin after discharge. CONCLUSION: It is easy to make a mistake in diagnosis because of the lacking of characteristic clinical manifestations. Exploratory operation immediately plus anticoagulant therapy is strongly recommended.