Targeted next-generation sequencing reveals activating CTNNB1 mutations in SMARCA4/BRG1-deficient sinonasal carcinomas: a report of two new cases and a brief review of the literature with an emphasis on histogenesis.

SMARCA4/BRG1 is a catalytic subunit of the SWItch/sucrose non-fermentable (SWI/SNF) complex and its inactivation is known to drive a variety of cancers across different organs. SMARCA4/BRG1-deficient carcinoma is a relatively new entity in the sinonasal region, and a comprehensive molecular investigation of the underlying genetic abnormalities is largely lacking. In this study, we report two new cases of SMARCA4/BRG1-deficient sinonasal carcinoma with targeted next-generation sequencing analysis, both of which revealed activating mutation of CTNNB1 in addition to somatic loss-of-function mutation of SMARCA4, providing further insights into its tumorigenesis and theoretical basis for the potential future targeted therapy. Activating CTNNB1 mutations in our cases may provide further evidence that SMARCA4-deficient sinonasal carcinoma, sinonasal teratocarcinosarcoma, and olfactory carcinoma are genetically closely related lesions, as recently proposed in the literature.

Mesonephric-Like Adenocarcinoma of Uterine Corpus: A Clinicopathological and Targeted Genomic Profiling Study in a Single Institution.

Background: Mesonephric-like adenocarcinoma (MLA) is a recently characterized, rare, and aggressive neoplasm that mostly arises in the uterine corpus and ovary. MLA shows characteristic pathological features similar to mesonephric adenocarcinoma of the cervix. The origin of MLA is still controversial and recognition of it remains challenging for pathologists. The aim of this study was to enrich the clinicopathological features of MLA in the uterine corpus and explore its molecular alterations by targeted next-generation sequencing (NGS). Methods: Four cases of MLA were identified among a total of 398 endometrial carcinomas diagnosed in our institution between January 2014 and December 2021. Immunohistochemistry and targeted NGS spanning 437 cancer-relevant genes were performed. Results: The most common symptom was abnormal vaginal bleeding, and the average age was 68 years. Histologically, the tumors showed a mixture of varied growth patterns including papillary, glandular, tubular, cribriform, solid, and slit-like architectures, which were lined by columnar to cuboidal cells with overlapping vesicular nuclei and sometimes nuclear grooves. Intraluminal eosinophilic colloid-like secretions were focally evident in three of the four cases. Immunohistochemically, the MLAs were positive for GATA3 (4/4), TTF-1 (3/3), luminal CD10 (3/3), calretinin (2/3), and patchy P16 (3/3) and were negative for ER (0/4) and PR (0/4). The expression of P53 was "wild type" (4/4). By targeted NGS, 3/4 (75%), 2/4 (50%), and 1/4 (25%) cases harbored PIK3CA, KRAS, and PTEN mutations, respectively. None of the tumors had mutations in DNA mismatch repair genes, ARID1A/B, POLE, CTNNB1, SMARCA4, or TP53. At the time of diagnosis, three were presented with FIGO IB stage and one with IIIC stage. Two patients received postoperative chemotherapy and radiotherapy and they were alive without evidence of disease at 8 and 56 months follow-up, respectively. One patient developed pulmonary metastasis 13 months after surgery and chemotherapy, and one was dead of the disease 24 months after the operation without adjuvant therapy. Conclusions: MLA is a rare and aggressive malignancy, representing approximately 1% of all endometrial carcinomas. It exhibits mixed architectures associated with distinctive immunophenotype and recurrent KRAS and PIK3CA mutations, supporting classified as of Müllerian origin with mesonephric differentiation.

Long non-coding RNA MAFG-AS1 promotes proliferation and metastasis of breast cancer by modulating STC2 pathway.

Breast cancer is the most common cancer worldwide. A number of studies proposed that long non-coding RNA plays an essential role in the regulation of invasion and metastasis of various forms of malignancy, including lung cancer, gastric cancer, and bladder cancer. In this study, a long non-coding RNA(LncRNA) MAFG-AS1 was explored in detail to understand the significance in the etiology of breast cancer. The results indicated that expression of LncRNA MAFG-AS1 in the breast cancer tissues was significantly higher than the adjacent normal breast tissues and elevated expression level of LncRNA MAFG-AS1 was correlated to the larger tumor size, negative expression of ER, PR and lymph node metastasis. The potency of breast cancer proliferation, invasion, and metastasis was inhibited in the absence of LncRNA MAFG-AS1. Mechanically, LncRNA MAFG-AS1 was mainly located in the cytoplasm. The downstream target gene of LncRNA MAFG-AS1 was STC2 which might promote cell proliferation and metastasis in breast cancer and this study provides a new potential therapeutic target for breast cancer.

Surgery for Cronkhite-Canada syndrome complicated with intussusception: A case report and review of literature.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare nonhereditary disease with a syndrome of multiple gastrointestinal polyps, skin pigmentation, hair loss, and fingernail/toenail dystrophy. Intussusception is a serious condition with an occurrence rate of 5% in adults, which is mainly caused by intestinal tumors or other intestinal occupations. CASE SUMMARY: A 57-year-old woman was admitted to our hospital due to abdominal distension and pain for the past year. Her nausea and vomiting symptoms had been aggravated for the past month. Previous transoral enteroscopy results one year prior showed chronic erosive gastritis protuberans, duodenitis, and jejunitis. She had sparse body hair and brown pigmentation on the skin of her hands and bilateral anterior tibias. The nails of both hands were pale and lacked luster, and the fingernail of her ring finger was longitudinally cracked. Gastroscopy showed extensive diffuse polypoid lump changes in the gastric body and antrum, of 0.5-3 cm in size. Colonoscopy showed multiple polypoid mucosal bulges in the terminal ileum and multiple polyps (0.3-5 cm) throughout the colon. The patient was diagnosed with CCS and underwent partial excision of the polyps, but she refused hormone therapy. One month later, the patient complained of nausea and vomiting, accompanied by abdominal pain and inability to pass gas or stool. Contrast-enhanced computed tomography of the abdomen showed gastrointestinal polyposis and ileocecal intussusception. She underwent stomach and bowel surgery. CONCLUSION: CCS, as a rare disease with poor prognosis, should be treated aggressively. Systematic steroids, immunosuppressive agents, and biological agents were not applied; thus, the patient's symptoms quickly progressed, and intussusception occurred. She had to undergo surgery. Improved compliance may lead to a better prognosis.

Characteristics and potential malignancy of colorectal juvenile polyps in adults: a single-center retrospective study in China.

BACKGROUND: Colorectal juvenile polyps are rare and generally considered benign in adults. Carcinogenesis or neoplastic changes are rarely mentioned in the literature. We systematically evaluated the characteristics and potential malignancy of colorectal juvenile polyps in adults. METHODS: We retrospectively reviewed the medical records of 103 adults diagnosed with colorectal juvenile polyps from September 2007 to May 2020 at our hospital. The characteristics, endoscopic findings, occurrence of intraepithelial neoplasia, carcinogenesis and diagnostic value of chicken skin mucosa (CSM) were analyzed. RESULTS: The average age of patients with juvenile polyps was 43.2 years (range, 19 to 78 years). A total of 101 patients (101/103, 98.1%) had a single juvenile polyp, and two patients had multiple polyps (107 polyps in total). Polyp sizes ranged from 0.5 to 5 cm. One (1/107, 0.9%) juvenile polyp was cancerous, and 7 (7/107, 6.5%) developed low-grade intraepithelial neoplasia. Neoplasia and cancerization did not appear in the two patients with multiple polyps. A 27-year-old female had a 2-cm polyp with well-differentiated adenocarcinoma in the mucosa in the sigmoid colon with erosion on the surface. CSM was observed adjacent to 17 polyps, which were all located in the rectum and sigmoid colon, and one polyp showed low-grade intraepithelial neoplasia. CONCLUSIONS: Colorectal juvenile polyps occur in a wide range of locations and in variable sizes and numbers. These polyps are solitary in most patients and have neoplastic potential. CSM is not a tumorigenic marker in colorectal juvenile polyps and usually occurs in the distant colorectum. Colorectal juvenile polyps in adults may progress from low-grade intraepithelial neoplasia to high-grade intraepithelial neoplasia and then to carcinoma and should be treated when discovered and regularly followed as colorectal adenomas.

Soft tissue perineurioma involving the kidney: a report of two cases with an emphasis on differential diagnosis.

BACKGROUND: Soft tissue perineurioma of the kidney is rare, with only a few reported cases. We report two additional cases with histologic, immunohistochemical and genetic analyses. CASE PRESENTATION: Both tumors were from adults (1 female aged 49 years and 1 male aged 42 years) and grossly had maximum diameters of 6.5 and 10 cm, respectively. The tumors were overall well circumscribed but unencapsulated, with focally entrapped benign native renal tubules in one case; both tumors seemed to arise in the capsular areas. The tumors had histologic and immunohistochemical profiles consistent with soft tissue perineurioma. Fluorescence in situ hybridization analyses demonstrated that the tumors were negative for amplification of MDM2 and rearrangements of ESWR1, FUS, and KMT2A. Targeted next-generation sequencing revealed a low tumor mutation burden and likely pathogenic mutations (CYP2B6 and FLT1 mutations for 1 each). Follow-up data were available for both patients; neither had tumor recurrence or metastasis. CONCLUSIONS: In conclusion, renal perineurioma is rare, usually arises in the capsular areas, and is cured by resection. Low-grade dedifferentiated liposarcoma and low-grade fibromyxoid sarcoma as well as other spindle cell lesions should be considered in the differential diagnosis.

Long intergenic non-coding RNA 00473 promotes proliferation and migration of gastric cancer via the miR-16-5p/CCND2 axis and by regulating AQP3.

Gastric cancer (GC) is one of the most common malignancies worldwide, but its molecular mechanisms remain unclear. Increasing evidence indicates that long non-coding RNAs (LncRNAs) play a pivotal role in various cancers recently. Our present study focused on exploring the function of long intergenic non-coding RNA 00473 (LINC00473) in GC. In this study, we found that LINC00473 expression was aberrantly increased in tumor tissues compared with the paired para-cancerous tissues. The expression of high LINC00473 in GC was notably correlated with a higher risk of lymphatic metastasis, a higher incidence of vascular cancer embolus, and advanced TNM stage. Further experiments showed that the overexpression of LINC00473 could promote the proliferation and metastasis of GC cells both in vitro and in vivo. The apoptosis of GC cells increased significantly by the decrease of LINC00473. Mechanistically, LINC00473 could sponge miR-16-5p in the cytoplasm and relieve its suppression of CCND2. Moreover, AQP3 was found to be a significant downstream target gene for LINC00473 through RNA transcriptome sequencing, as demonstrated by qRT-PCR and western blot. Overexpression of LINC00473 can partially reverse the effects of AQP3 decrease on GC proliferation and metastasis. LINC00473 regulated AQP3 expression through CREB was confirmed by western blot. Our research indicates that LINC00473/miR-16-5p/CCND2 axis plays a role in the proliferation of GC and modulates AQP3 to influence GC cell metastasis, making it a potential therapeutic target for GC.

Preoperative Prediction of Microvascular Invasion in Hepatocellular Carcinoma via Multi-Parametric MRI Radiomics.

OBJECTIVES: To systematically evaluate and compare the predictive capability for microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients based on radiomics from multi-parametric MRI (mp-MRI) including six sequences when used individually or combined, and to establish and validate the optimal combined model. METHODS: A total of 195 patients confirmed HCC were divided into training (n = 136) and validation (n = 59) datasets. All volumes of interest of tumors were respectively segmented on T2-weighted imaging, diffusion-weighted imaging, apparent diffusion coefficient, artery phase, portal venous phase, and delay phase sequences, from which quantitative radiomics features were extracted and analyzed individually or combined. Multivariate logistic regression analyses were undertaken to construct clinical model, respective single-sequence radiomics models, fusion radiomics models based on different sequences and combined model. The accuracy, sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were calculated to evaluate the performance of different models. RESULTS: Among nine radiomics models, the model from all sequences performed best with AUCs 0.889 and 0.822 in the training and validation datasets, respectively. The combined model incorporating radiomics from all sequences and effective clinical features achieved satisfactory preoperative prediction of MVI with AUCs 0.901 and 0.840, respectively, and could identify the higher risk population of MVI (P < 0.001). The Delong test manifested significant differences with P < 0.001 in the training dataset and P = 0.005 in the validation dataset between the combined model and clinical model. CONCLUSIONS: The combined model can preoperatively and noninvasively predict MVI in HCC patients and may act as a usefully clinical tool to guide subsequent individualized treatment.

The long noncoding RNA TINCR promotes breast cancer cell proliferation and migration by regulating OAS1.

Breast cancer is the leading cause of cancer-related death in women around the world. It is urgently needed to identify genes associated with tumorigenesis and prognosis, as well as to elucidate the molecular mechanisms underlying the oncogenic process. Long noncoding RNAs (lncRNAs) are widely involved in the pathological and physiological processes of organisms and play an important role as oncogenes or tumor suppressor genes, affecting the development and progression of tumors. In this study, we focused on terminal differentiation-induced non-coding RNA (TINCR) (GeneID:257000) and explore its role in the pathogenesis of breast cancer. The results showed that TINCR was increased in breast cancer tissue, and high expression level of TINCR was associated with older age, larger tumor size, and advanced TNM stage. High level of TINCR can promote proliferation and metastasis of breast cancer cells, while downregulation of TINCR induces G1-G0 arrest and apoptosis. Mechanismly, TINCR can bind to staufen1 (STAU1) and then guide STAU1 (GeneID:6780) to bind to OAS1 mRNA (NM_016816.4) to mediate its stability. Thus low level of OAS1(GeneID:4938) can lead to cell proliferation and migration. This result elucidates a new mechanism for TINCR in breast cancer development and provides a survival indicator and potential therapeutic target for breast cancer patients.

The long intergenic non-protein coding RNA 707 promotes proliferation and metastasis of gastric cancer by interacting with mRNA stabilizing protein HuR.

Multiple studies have revealed that long non-coding RNAs (lncRNAs) extensively participate in human cancer malignant progression. The long intergenic non-protein coding RNA 707 (LINC00707), 3087 bp in length, was recently reported to be an essential oncogene in promoting lung adenocarcinoma cell proliferation and metastasis. However, its role in gastric cancer (GC) remains unclear. In this study, we identified that LINC00707 was excessively expressed in GC tissues and correlated with advanced stage, larger tumor size, lymph node metastasis and poorer prognosis in GC patients. In vitro and in vivo assays showed that LINC00707 promote GC cell proliferation and metastasis. Mechanistically, LINC00707 could abundantly interact with mRNA stabilizing protein HuR; "LINC00707-HuR" coalition ulteriorly combined with VAV3/F11R mRNAs and increased their stability. Taken together, our findings prove that LINC00707 may act as an oncogene in GC by regulating mRNA stability and serve as a potential target for GC diagnosis and prognosis.

Long intergenic non-coding RNA 00324 promotes gastric cancer cell proliferation via binding with HuR and stabilizing FAM83B expression.

Substantial evidence shows that long non-coding RNAs (lncRNAs) participate in many biological mechanisms, and their dysregulation are also involved in the development and progression of cancers, including gastric cancer (GC). Long intergenic non-coding RNA 00324 (LINC00324), a 2115 bp ncRNA, is located on chromosome 17p13.1. The biological function and molecular mechanisms of LINC00324 in GC remains undiscovered. In this paper, we found that the expression level of LINC00324 was significantly upregulated in GC tissues compared with the corresponding normal tissues. The overexpression of LINC00324 was correlated with advanced TNM stage, larger tumor size, and lymph node metastasis as well as poor prognosis. Further experiments revealed that knockdown of LINC00324 could suppress the proliferation of GC cells. RNA transcriptome sequencing technology revealed that FAM83B may be a significant downstream target gene of LINC00324. LINC00324 could combine with the RNA-binding protein (RBP) human antigen R (HuR) and thus stabilize the expression of FAM83B. Moreover, rescue assays showed that the reduced FAM83B expression partially reversed the promotion of cell growth in GC induced by the overexpression of LINC00324. In conclusion, our study revealed that LINC00324 acted as an oncogene in tumorigenesis and progression, suggesting that it could be a new biomarker in diagnosis and prognosis of GC.

The pseudogene-derived long non-coding RNA SFTA1P suppresses cell proliferation, migration, and invasion in gastric cancer.

Pseudogenes were once regarded as transcriptionally inactive and without specific molecular function. However, current evidence shows that pseudogene-derived long non-coding RNAs (lncRNAs) may be crucial regulators of human cancer development, including gastric cancer (GC). In the present study, we report that a pseudogene-derived lncRNA named surfactant associated 1, pseudogene (SFTA1P), which is 693-nt long, was significantly down-regulated in GC tissues compared with that in the adjacent normal tissues. In addition, decreased SFTA1P expression was strongly correlated with advanced tumor lymph node metastasis (TNM) stage, larger tumor size, lymphatic metastasis, and poor prognosis of patients with GC. Moreover, gain-of-function experiments revealed that the overexpression of SFTA1P inhibits cell proliferation, migration, and invasion, thus verifying the tumor inhibitory role of SFTA1P in GC. Furthermore, we investigated the potential action mechanism of SFTA1P. Our results showed that down-regulation of SFTA1P may be associated with decreased TP53 expression. In summary, our work suggests that the pseudogene-derived lncRNA SFTA1P functions as a tumor suppressor in GC and thus may act as a potential diagnostic and therapeutic target of GC.

The Long Intergenic Noncoding RNA 00707 Promotes Lung Adenocarcinoma Cell Proliferation and Migration by Regulating Cdc42.

BACKGROUND/AIMS: Lung cancer (LC) is a serious disease with high morbidity and mortality. Long noncoding RNAs (lncRNAs) have garnered attention because they participate in diverse human disorders, including cancer. Our study examined the long intergenic noncoding RNA 00707 (LINC00707). The effects of LINC00707 on lung adenocarcinoma (LAD) and molecular mechanisms are unclear. This study is aimed to investigate the role of LINC00707 in the malignant processes of LAD. METHODS: Quantitative reverse transcription PCR (qRT-PCR) was used to examine the expression level of LINC00707 in tissues and cell lines. The association of LINC00707 expression and postoperative prognosis was analyzed by the Kaplan-Meier method and log-rank test. Cell proliferation was evaluated in vitro and in vivo. Transwell assays were performed to examine cell migration. Cell cycle and apoptosis was determined by flow -cytometric and western blot analyses. Microarray analysis was conducted to screen for the downstream target gene Cdc42 of LINC00707, which was identified by qRT-PCR, functional analysis, and rescue experiment. RESULTS: The expression level of LINC00707 was clearly upregulated in LAD tissues compared to that in corresponding normal tissues. Its overexpression was related to advanced TNM stage, larger tumor size, lymphatic metastasis, and poor prognosis. Functional assays revealed that LINC00707 knockdown repressed LAD cell proliferation both in vitro and in vivo. This process may involve the inducing of G1 arrest and apoptosis. Moreover, cell migration was impaired after LINC00707 inhibition. Microarray analysis and rescue assays suggested that Cdc42 is an important target gene involved in the carcinogenesis of LINC00707. CONCLUSIONS: In summary, LINC00707 is a noncoding oncogene that exerts important regulatory functions in LAD, suggesting its potential as a biomarker in the prognosis and treatment of LAD.

The pseudogene derived long noncoding RNA DUXAP8 promotes gastric cancer cell proliferation and migration via epigenetically silencing PLEKHO1 expression.

Gastric cancer (GC) is the third leading cause of cancer death due to its poor prognosis and limited treatment options. Evidence indicates that pseudogene-derived long noncoding RNAs (lncRNAs) may be important players in human cancer progression, including GC. In this paper, we report that a newly discovered pseudogene-derived lncRNA named DUXAP8, a 2107-bp RNA, was remarkably upregulated in GC. Additionally, a higher level of DUXAP8 expression in GC was significantly associated with greater tumor size, advanced clinical stage, and lymphatic metastasis. Patients with a higher level of DUXAP8 expression had a relatively poor prognosis. Further experiments revealed that knockdown of DUXAP8 significantly inhibited cell proliferation and migration, as documented in the SGC7901 and BGC823 cell lines. Furthermore, RNA immunoprecipitation and chromatin immunoprecipitation assays demonstrated that DUXAP8 could epigenetically suppress the expression of PLEKHO1 by binding to EZH2 and SUZ12 (two key components of PRC2), thus promoting GC development. Taken together, our findings suggest that the pseudogene-derived lncRNA DUXAP8 promotes the progression of GC and is a potential therapeutic target for GC intervention.

Mulberry leaf alleviates streptozotocin-induced diabetic rats by attenuating NEFA signaling and modulating intestinal microflora.

Improvement of hyperglycemia through dietotherapy/herbal remedy is an effective approach to treating diabetes. In this study, mulberry leaf, famous for silkworm's special food and therapeutic value without any side effects, alleviated diabetes by attenuating NEFA signaling and modulating intestinal microflora. Mulberry leaf treatment significantly reduce fasting blood-glucose and HbA1c, ameliorate the blood lipid profile and improve insulin resistance in streptozotocin-induced diabetic rats. Mechanistically, we found that mulberry leaf inhibited NEFA signaling by reducing downstream signaling in the NEFA pathway, further verified by reduced PKC and improved cellular energy homeostasis based on restored expression of PGC-1α, AK2, OXPHOS and adiponectin. Mulberry leaf treatment also restored the phyla Bacteroidetes and Proteobacteria and class Clostridia, which were associated with insulin resistance and diabetes. Our findings reveal that mulberry leaf is an edible with therapeutic potential for diabetes and may provide a novel dietotherapy/herbal remedy to the treatment of diabetes.