As one of the leading causes of cancer-related deaths, gastric cancer (GC) has gained more and more attention. Although most GCs are adenocarcinomas, they have considerable heterogeneity among patients. Thus, appropriate classification and individualized treatment of GCs is essential. The traditional morphology-based classification systems including the World Health Organization (WHO) classification and the Lauren's classification have a limited utility in guiding clinical treatment due to the molecular heterogeneity of GC. Classifications based on molecular features become important. Recent years, molecular methods such as next-generation sequencing (NGS) including deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, whole-exome sequencing, copy number variation analysis and DNA methylation arrays have been used to classify the GC into molecular subtypes which can convey more detailed information of tumor than histopathological characteristics. In this review, we described the current molecular classifications of GC including the intrinsic subtypes, Lei subtypes, The Cancer Genome Atlas (TCGA) subtypes, Asian Cancer Research Group (ACRG) subtypes, and some other additional classifications.

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Molecular Classification of Gastric Adenocarcinoma.

Over the last years, epigenetic changes, including DNA methylation and histone modifications detected in early tumorigenesis and cancer progression, have been proposed as biomarkers for cancer detection, tumor prognosis, and prediction to treatment response Importantly for the clinical use of DNA methylation biomarkers, specific methylation signatures can be detected in many body fluids including serum/plasma samples Several of these potential epigenetic biomarkers detected in women's cancers, colorectal cancers, prostate, pancreatic, gastric, and lung cancers are discussed Studies conducted in breast cancer, for example, found that aberrant methylation detection of several genes in serum DNA and genome-wide epigenetic change could be used for early breast cancer diagnosis and prediction of breast cancer risk In colorectal cancers, numerous studies have been conducted to identify specific methylation markers important for CRC detection and in fact clinical assays evaluating the methylation status of SEPT19 gene and vimentin, became commercially available Furthermore, some epigenetic changes detected in gastric washes have been suggested as potential circulating noninvasive biomarkers for the early detection of gastric cancers For the early detection of prostate cancer, few epigenetic markers have shown a better sensitivity and specificity than serum PSA, indicating that the inclusion of these markers together with current screening tools, could improve early diagnosis and may reduce unnecessary repeat biopsies Similarly, in pancreatic cancers, abnormal DNA methylation of several genes including NPTX2, have been suggested as a diagnostic biomarker Epigenetic dysregulation was also observed in several tumor suppressor genes and miRNAs in lung cancer patients, suggesting the important role of these changes in cancer initiation and progression In conclusion, epigenetic changes detected in biological fluids could play an essential role in the early detection of several cancer types and this may have a great impact for the cancer precision medicine field

Early Epigenetic Markers for Precision Medicine.

// Haochang Hu 1, * , Xiaoying Chen 1, * , Cheng Wang 2, * , Yuting Jiang 1 , Jingjing Li 3 , Xiuru Ying 1 , Yong Yang 1 , Bin Li 1 , Cong Zhou 1 , Jie Zhong 1 , Dongping Wu 2 , Jieer Ying 3 and Shiwei Duan 1 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China 2 Department of Medical Oncology, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Zhejiang 312000, China 3 Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China * Co-first authors Correspondence to: Shiwei Duan, email: duanshiwei@nbu.edu.cn Jieer Ying, email: jieerying@aliyun.com Keywords: tissue factor pathway inhibitor 2, DNA methylation, gastric cancer, colorectal cancer, quantitative methylation-specific polymerase chain reaction Received: November 30, 2016      Accepted: August 28, 2017      Published: September 20, 2017 ABSTRACT Gastrointestinal cancer is a prevalent disease with high morbidity and mortality. Tissue factor pathway inhibitor 2 ( TFPI2 ) gene could protect the extracellular matrix of cancer cells from degradation and tumor invasion. The goal of our study was to estimate the diagnostic value of TFPI2 hypermethylation in gastric cancer (GC) and colorectal cancer (CRC). TFPI2 methylation was measured by quantitative methylation-specific polymerase chain reaction (qMSP) method in 114 GC and 80 CRC tissues and their paired non-tumor tissues. Our results showed that TFPI2 methylation was significantly higher in tumor tissues (GC: 29.940% vs. 12.785%, P 1.37). In conclusion, TFPI2 hypermethylation might be a promising diagnostic biomarker for GC and CRC.

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The role of TFPI2 hypermethylation in the detection of gastric and colorectal cancer

Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor that has been firmly associated with colorectal cancer (CRC) initiation and development. STAT3 mediates key inflammatory mechanisms in colitis-associated cancer, becomes excessively activated in CRC, and enhances cancer cell proliferation, tumor growth, angiogenesis, invasion, and migration. STAT3 hyperactivation in malignant cells, surrounding immune cells and cancer-associated fibroblasts, mediates inhibition of the innate and adaptive immunity of the tumor microenvironment, and, therefore, tumor evasion from the immune system. These features highlight STAT3 as a promising therapeutic target; however, the mechanisms underlying these features have not been fully elucidated yet and STAT3 inhibitors have not reached the clinic in everyday practice. In the present article, we review the STAT3 signaling network in CRC and highlight the current notion for the design of STAT3-focused treatment approaches. We also discuss recent breakthroughs in combination immunotherapy regimens containing STAT3 inhibitors, therefore providing a new perception for the clinical application of STAT3 in CRC.

Targeting STAT3 Signaling Pathway in Colorectal Cancer.

Gastric cancer is one of the most common causes of death worldwide, although its incidence has steadily declined in recent years. There is strong evidence that aberrantly expressed microRNAs (miRNAs) are involved in gastric cancer tumorigenesis. Furthermore, CRMP4 is closely associated with the occurrence and development of gastric cancer, and our predictions suggest that miR-130a, which can promote gastric cancer tumorigenesis, is a potential CRMP4 regulator. In this study, we investigated the expression of CRMP4 and miR-130a in human gastric cancer cell lines by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB) examination and direct interactions between miR-130a and CRMP4 by dual-luciferase reporter assay. We also evaluated the biological roles of miR-130a and CRMP4 in gastric cancer cells by flow cytometry, MTT assay, soft agar colony formation assay, and Transwell tests and confirmed CRMP4 function in vivo, using a tumor xenograft model. Our results demonstrated that CRMP4 expression was significantly decreased at both the gene and protein levels, while miR-130a expression was notably increased, in five human gastric cancer cell lines compared with human gastric epithelial cells. Dual-luciferase reporter assays indicated that CRMP4 was the direct target of miR-130a. Moreover, an inverse regulatory relationship between miR-130a and CRMP4 was verified by qRT-PCR and WB, and overexpression of miR-130a in BGC823 cells enhanced apoptosis and cell proliferation, arrested the cell cycle in G0/G1, and facilitated cell colony formation, invasion, migration, and adhesion, while upregulation of CRMP4 had opposite effects. Finally, the growth and weight of transplanted tumors derived from BGC823 cells in which CRMP4 was knocked down were remarkably reduced. These data indicate that miR-130a is an oncomir targeting CRMP4 and could be developed as a potential prognostic factor and a novel therapeutic target in gastric cancer.

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microRNA-130a is an oncomir suppressing the expression of CRMP4 in gastric cancer.

Colorectal cancer (CRC) is a major cause of cancer mortality worldwide, however, the molecular mechanisms underlying the pathogenesis of CRC remain largely unclear. Recent studies have revealed crucial roles of transcription factors in CRC development. Transcription factors essential for the regulation of gene expression by interacting with transcription corepressor/enhancer complexes and they orchestrate downstream signal transduction. Deregulation of transcription factors is a frequent occurrence in CRC, and the accompanying drastic changes in gene expression profiles play fundamental roles in multistep process of tumorigenesis, from cellular transformation, disease progression to metastatic disease. Herein, we summarized current and emerging key transcription factors that participate in CRC tumorigenesis, and highlighted their oncogenic or tumor suppressive functions. Moreover, we presented critical transcription factors of CRC, emphasized the major molecular mechanisms underlying their effect on signal cascades associated with tumorigenesis, and summarized of their potential as molecular biomarkers for CRC prognosis therapeutic response, as well as drug targets for CRC treatment. A better understanding of transcription factors involved in the development of CRC will provide new insights into the pathological mechanisms and reveal novel prognostic biomarkers and therapeutic strategies for CRC.

Transcription factors in colorectal cancer: molecular mechanism and therapeutic implications

Gastric cancer development follows the pathologic pattern such that chronic inflammation in the gastric mucosa progressively transforms normal mucosa into atrophy, intestinal metaplasia, adenoma/dysplasia and eventually invasive and metastatic tumors. The accumulation of multiple genetic and epigenetic alterations leads to the dysregulation of oncogenes and tumor suppressors, which was considered as the driver behind events during the tumorigenesis. Almost all gastric cancers are adenocarcinomas, which share considerable heterogeneity with distinct morphology, pathogenesis and clinical behavior. Therefore, identifying subtypes of gastric cancers with molecular and genetic features will be beneficial for the early identification and selection of new effective agents for targeted treatment. High-throughput sequencing techniques such as whole genomic, epigenome and transcriptome sequencing and proteomics platforms have identified major genomic characteristics that exhibit identification and prognostic impacts and distinct response patterns. In this article, the authors aim to summarize the information regarding the most promising molecules that may have clinical application as non-invasive biomarkers and therapy targets.

Novel biomarkers for the identification and targeted therapy of gastric cancer

RNF6 is a RING finger protein with oncogenic potential. In this study, we established colon-specific RNF6 transgenic (tg) mice, and demonstrated that RNF6 overexpression accelerated colorectal carcinogenesis compared to wild-type littermates in a chemically induced colorectal cancer (CRC) model. To understand whether transcriptional activity of RNF6 underlies its oncogenic effect, we performed integrated chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing analysis to identify splicing factor 3b subunit 2 (SF3B2) as a potential downstream target of RNF6. RNF6 binds to the SF3B2 promoter and the overexpression of RNF6 activates SF3B2 expression in CRC cells, primary CRC organoids, and RNF6 tg mice. SF3B2 knockout abrogated the tumor promoting effect of RNF6 overexpression, whereas the reexpression of SF3B2 recused cell growth and migration/invasion in RNF6 knockout cells, indicating that SF3B2 is a functional downstream target of RNF6 in CRC. Targeting of RNF6-SF3B2 axis with SF3B2 inhibitor with pladienolide B suppressed the growth of CRC cells with RNF6 overexpression in vitro and in vivo. Moreover, the combination of 5-fluorouracil (5-FU) plus pladienolide B exerted synergistic effects in CRC with high RNF6 expression, leading to tumor regression in xenograft models. These findings indicate that tumor promoting effect of RNF6 is achieved mainly via transcriptional upregulation of SF3B2, and that RNF6-SF3B2 axis is a promising target for CRC therapy.

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Lei Liu

Papers

Transcription factors in colorectal cancer: molecular mechanism and therapeutic implications

Novel biomarkers for the identification and targeted therapy of gastric cancer

RING-finger protein 6 promotes colorectal tumorigenesis by transcriptionally activating SF3B2.