• ADO
• IFN-γ
• Immune surveillance
• PD-1/PD-L1
• Sirt6
• Tregs
• Tumor microenvironment

• Alzheimer’s disease
• Beta amyloid
• Electron microscopy
• Immunohistochemistry
• Mild cognitive impairment
• Plaques
• Preclinical
• SMOC1
• Tangles
• Tau
• Thioflavin T

• Humans
• Alzheimer Disease/pathology
• Alzheimer Disease/metabolism
• Amyloid beta-Peptides/metabolism
• Female
• Aged
• Male
• Aged, 80 and over
• Brain/pathology
• Brain/metabolism
• Cognitive Dysfunction/pathology
• Cognitive Dysfunction/metabolism
• tau Proteins/metabolism
• Plaque, Amyloid/pathology
• Plaque, Amyloid/metabolism
• Protein Aggregation, Pathological/pathology
• Protein Aggregation, Pathological/metabolism
• Middle Aged

• DP200102463 Australian Research Council
• R01 AG017917 NIA NIH HHS
• P01 AG060882 NIA NIH HHS
• FMH EMCR Emerging Star Grant Faculty of Medicine and Health, University of Sydney
• P01AG060882 NIH, USA
• R01AG017917 NIH, USA
• Blas Frangione Early Career Award Alzheimer's Association
• Bluesand Foundation
• University of Sydney Centre for Drug Discovery Innovation
• Alzheimer’s Association
• University of Sydney

• Alzheimer’s Disease
• SMOC1
• beta amyloid
• electron microscopy
• immunohistochemistry
• mild cognitive impairment
• plaques
• preclinical
• tangles
• tau
• thioflavin T

• P30 AG072975 NIA NIH HHS
• P30 AG066512 NIA NIH HHS
• R01 AG017917 NIA NIH HHS
• P30 AG010161 NIA NIH HHS
• P01 AG060882 NIA NIH HHS

• Colorectal cancer
• SMOC1
• Serrated lesion
• Traditional serrated adenoma

• Humans
• Adenoma/genetics
• Adenoma/pathology
• Colonic Polyps/pathology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Down-Regulation
• Hyperplasia
• Osteonectin
• Proto-Oncogene Proteins B-raf/genetics

• JSPS KAKENHI 22K07964 Japan Society for the Promotion of Science
• JSPS KAKENHI 21K07985 Japan Society for the Promotion of Science
• JSPS KAKENHI 20K07662 Japan Society for the Promotion of Science
• JSPS KAKENHI 20K08335 Japan Society for the Promotion of Science
• JSPS KAKENHI 22H02925 Japan Society for the Promotion of Science

• Humans
• Anus Neoplasms/pathology
• Anus Neoplasms/therapy
• Rectal Neoplasms/pathology
• Rectal Neoplasms/therapy
• Rectal Neoplasms/diagnosis
• Colonic Neoplasms/pathology

• colorectal cancer
• obesity

• colorectal cancer
• serum amyloid A1
• tumor microenvironment
• tumor-associated macrophage
• tumor-associated neutrophil

• 450 K bead assay
• Biomarkers
• DNA methylation
• Epigenetics
• Epityper MassArray
• Stomach cancer

• Estrogen receptor
• HOX genes
• HOXA1
• Regulatory network
• breast cancer

Background: Secreted modular calcium-binding protein 1 (SMOC1) belongs to a family of matricellular proteins; it was involved in embryo development, endothelial cell proliferation, angiogenesis, integrin–matrix interactions, cell adhesion, and regulation of glucose metabolism. Previous studies showed that the expression of SMOC1 was increased in some tumors. However, the prognostic value and the biological function of SMOC1 in tumor remain unclear.

Methods: In this study, we explored the expression profile and prognostic value of SMOC1 in pan-cancers, especially glioma, via multiple databases, including Oncomine, Gene Expression Profiling Interactive 2, PrognoScan, Kaplan–Meier plotter, and the Chinese Glioma Genome Atlas database. Furthermore, LinkedOmics was used to identify the genes coexpressed with SMOC1 and to perform Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology analysis in low-grade glioma (LGG). Also, the Cancer Single-Cell State Atlas database was used to evaluate the correlation between SMOC1 expression and functional state activities in glioma cells. In addition, the Tumor Immune Estimation Resource and TISIDB databases were used to evaluate the correlations between SMOC1 expression and tumor-infiltrating immune cells in the tumor microenvironment.

Results: Compared with normal brain tissues, the expression of SMOC1 was increased in LGG tissues. The higher expression of SMOC1 was significantly correlated with better survival of LGG patients. Additionally, functional analyses showed that the SMOC1 coexpressed genes were inhibited in processes such as response to type I interferon and interferon-gamma, lymphocyte-mediated immunity, leukocyte migration, adaptive immune response, neutrophil-mediated immunity, T cell activation, and pathways including EMC–receptor interaction, Th17 cell differentiation, and leukocyte trans-endothelial migration in LGG. Moreover, the expression of SMOC1 was correlated with stemness, hypoxia, EMT, and metastasis of glioma cells. Additionally, the expression of SMOC1 expression was negatively correlated with levels of infiltrating B cells, CD8⁺ T cells, CD4⁺ T cells, macrophages, neutrophils and dendritic cells, and gene markers of most immune cells in LGG.

Conclusion: Our results suggest that SMOC1 could be a potential biomarker to determine prognosis and might play a specific role in the tumor microenvironment of glioma, thereby influencing the development and progression of glioma. These findings provide some new insights for further investigation.

• SMOC1
• biological function
• low-grade glioma
• prognostic value
• tumor microenvironment

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA‐sequencing (RNA‐seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Coculture experiments using CRC cell lines and THP‐1 cells suggested that interleukin 1β (IL‐1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL‐1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1‐like/M2‐like macrophages at SAA1‐positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of matrix metalloproteinase‐9 in macrophages. Our data suggest that tumor‐associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1 and that SAA1 may be a predictive biomarker and a useful therapeutic target.

• colorectal cancer
• serum amyloid A1
• submucosal invasion
• tumor microenvironment
• tumor-associated macrophage

• Colonic Polyps
• Humans
• Mutation
• Neoplasms
• Proto-Oncogene Proteins B-raf/genetics

Traditional serrated adenoma was first reported by Longacre and Fenoglio-Presier in 1990. Their initial study described main features of this lesion, but the consensus diagnostic criteria were not widely adopted until recently. Traditional serrated adenoma presents with grossly protuberant configuration and pinecone-like appearance upon endoscopy. Histologically, it is characterized by ectopic crypt formation, slit-like serration, eosinophilic cytoplasm and pencillate nuclei. Although much is now known about the morphology and molecular changes, the mechanisms underlying the morphological alterations are still not fully understood. Furthermore, the origin of traditional serrated adenoma is not completely known. We review recent studies of the traditional serrated adenoma and provide an overview on current understanding of this rare entity.

• Traditional serrated adenoma
• Serrated polyps
• KRAS
• BRAF
• Colon

Tumor angiogenesis is an important therapeutic target in colorectal cancer (CRC). We aimed to identify novel genes associated with angiogenesis in CRC. Using RNA sequencing analysis in normal and tumor endothelial cells (TECs) isolated from primary CRC tissues, we detected frequent upregulation of adipocyte enhancer‐binding protein 1 (AEBP1) in TECs. Immunohistochemical analysis revealed that AEBP1 is upregulated in TECs and stromal cells in CRC tissues. Quantitative RT‐PCR analysis showed that there is little or no AEBP1 expression in CRC cell lines, but that AEBP1 is well expressed in vascular endothelial cells. Levels of AEBP1 expression in Human umbilical vein endothelial cells (HUVECs) were upregulated by tumor conditioned medium derived from CRC cells or by direct coculture with CRC cells. Knockdown of AEBP1 suppressed proliferation, migration, and in vitro tube formation by HUVECs. In xenograft experiments, AEBP1 knockdown suppressed tumorigenesis and microvessel formation. Depletion of AEBP1 in HUVECs downregulated a series of genes associated with angiogenesis or endothelial function, including aquaporin 1 (AQP1) and periostin (POSTN), suggesting that AEBP1 might promote angiogenesis through regulation of those genes. These results suggest that upregulation of AEBP1 contributes to tumor angiogenesis in CRC, which makes AEBP1 a potentially useful therapeutic target.

• angiogenesis
• aquaporin 1
• cancer stroma
• periostin
• tumor endothelium

Secreted modular calcium-binding proteins (SMOCs) are extracellular glycoproteins of the secreted protein, acidic, and rich in cysteine-related modular calcium-binding protein family and include two isoforms, SMOC1 and SMOC2, in humans. Functionally, SMOCs bind to calcium for various cell functions. In this review, we provided a summary of the most recent advancements in and findings of SMOC1 and SMOC2 in development, homeostasis, and disease states.

All publications in the PubMed database were searched and retrieved (up to July 24, 2019) using various combinations of keywords searching, including SMOC1, SMOC2, and diseases.

All original studies and review articles of SMOCs in human diseases and embryo development written in English were retrieved and included.

SMOC1 and SMOC2 regulate embryonic development, cell homeostasis, and disease pathophysiology. They play an important role in the regulation of cell cycle progression, cell attachment to the extracellular matrix, tissue fibrosis, calcification, angiogenesis, birth defects, and cancer development.

SMOC1 and SMOC2 are critical regulators of many cell biological processes and potential therapeutic targets for the control of human cancers and birth defects.

• BRAF
• V600E
• clinicopathological
• colorectal polyp
• serrated adenoma

• Adenoma/genetics
• Adenoma/pathology
• Aged
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Female
• Humans
• Male
• Middle Aged
• Mutation
• Proto-Oncogene Proteins B-raf/genetics

To provide an overview of the pathology and molecular pathogenesis of traditional serrated adenomas (TSA).

Describe the morphology and molecules that play a role in their pathogenesis.

These exuberant polypoid lesions are typified by tall cells with deeply eosinophilic cytoplasm, elongated nuclei bearing delicate chromatin, ectopic crypt foci, deep clefting of the lining mucosa and an overall resemblance to small bowel mucosa.

Broadly, TSAs arise via three mechanisms. They may be BRAF mutated and CpG island methylator phenotype (CIMP)-high: right sided, mediated through a microvesicular hyperplastic polyp or a sessile serrated adenoma, may also have RNF43 mutations and result in microsatellite stable (MSS) colorectal cancers (CRC). The second pathway that is mutually exclusive of the first is mediated through KRAS mutation with CIMP-low TSAs. These are left-sided TSAs, are not associated with another serrated polyp and result in MSS CRC. These TSAs also have RSPO3, RNF43 and p53 mutations together with aberrant nuclear localisation of β-catenin. Third, there is a smaller group of TSAs that are BRAF and KRAS wild type and arise by as yet unknown molecular events. All TSAs show retention of mismatch repair proteins.

These are characteristic unusual polyps with a complex molecular landscape.

• BRAF
• KRAS
• colorectal cancer
• serrated polyp
• traditional serrated adenoma

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the “serrated pathway”, has been described. Approximately, 15 to 30% of all CRCs arise from neoplastic serrated polyps, a heterogeneous group of lesions that are histologically classified into three morphologic categories: hyperplastic polyps, sessile serrated adenomas/polyps, and the traditional serrated adenomas/polyps. Serrated polyps are characterized by genetic (BRAF or KRAS mutations) and epigenetic (CpG island methylator phenotype (CIMP)) alterations that cooperate to initiate and drive malignant transformation from normal colon mucosa to polyps, and then to CRC. The high heterogeneity of the serrated lesions renders their diagnostic and pathological interpretation difficult. Hence, novel genetic and epigenetic biomarkers are required for better classification and management of CRCs. To date, several molecular alterations have been associated with the serrated polyp-CRC sequence. In addition, the gut microbiota is emerging as a contributor to/modulator of the serrated pathway. This review summarizes the state of the art of the genetic, epigenetic and microbiota signatures associated with serrated CRCs, together with their clinical implications.

• CIMP
• CIN
• DNA methylation
• MSI
• colorectal cancer
• gut microbiota
• serrated adenocarcinoma
• serrated lesions
• serrated pathway
• serrated polyp

• Eph gene
• Notch signaling
• colorectal cancer
• histone methylation