Frequent amplification of 7q21-22 genomic region is known in gastric cancer. Multiple genes including SHFM1, MCM7, and COL1A2 were reported to be the potential cancer candidate genes of this 20 Mb amplicon. This amplicon has two polycistrionic miRNA clusters and in the present study, miR-106b-25 cluster located in intron-13 of MCM7 was identified to express in gastric tumors. Among the 7q21-22 candidate genes, SHFM1 and MCM7 are expressed in intestinal type gastric tumors, whereas COL1A2 is expressed in diffuse type gastric tumors. Across gastric tumors, miR-25 was identified to co-express with MCM7 and SHFM1. On the other hand, negative correlation was observed between miR-25 and COL1A2 expression. miR-25 originating from MCM7 was found capable of selectively targeting the adjacent gene COL1A2. Silencing of miR-25 was found capable of elevating the expression of COL1A2 and inhibiting E-cadherin expression, revealing the diffuse type gastric cancer suppressive role conferred by miR-25. miR-25 was also found to suppress p53, and activate c-Src revealing its intestinal type gastric cancer associated oncogenic functions. Genome-wide expression profiling upon miR-25 silencing reveals that miR-25 is capable of suppressing 40 genes which are co-expressed with COL1A2, involved in epithelial to mesenchymal transition and angiogenesis which are the typical diffuse type gastric cancer features. The results clearly demonstrate 7q21-22 amplification, MCM7, and its intronic miR-25 are the major molecular switches involved in the complex oncogenic circuits of gastric cancer.

The existing large number of gene expression profiles of tumour samples offers a great advantage for the integrative functional genomic exploration of molecular dysregulation in cancers. The clusters of genes (modules) derived from a gastric cancer (GC) coexpression network were explored to understand their clinical and functional significance. Among the modules derived from the GC mRNA expression network, six modules were relatively highly expressed in diffuse type gastric tumours. Elevated expression of genes related to extracellular matrix (ECM), angiogenesis, collagen and intracellular cytoskeletal components and immune response were identified in these modules. ECM-related modules exhibited an inverse correlation with modules representing the expression of immune response genes. A reduced expression of immune response genes was identified as the key factor associated with the aggressive features of diffuse gastric tumours, which is indicative of tumour progression involving the escape from immune surveillance in diffuse tumours. A part of the identified aggressive factors was common between intestinal and diffuse type tumours. The coexpressed modules and their expression patterns delineate the fine transition involved in cancer progression in the later stages of tumours. The identified modules could serve as surrogate gene-sets, indicating the molecular staging of GC aggressiveness with underlying biological interaction.

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HIF1 is a transcription factor activated under hypoxic condition in many cancer types and has been implicated in cancer cell proliferation, invasion and energy metabolism. Towards understanding the role of HIF1 mediated transcription in gastric cancer, the HIF1 gene signatures established to date were analyzed for their expression across the mRNA profiles of gastric tumors. HIF1 regulated genes were identified to involve and associated with the signaling pathways and processes such as integrin signaling, Wnt, P53, EGF, FGF, VEGFA, PI3K, TGFβ and NFkB signaling pathways. The HIF1a genes were identified to play a significant role in energy metabolism including glycolysis, drug resistance due to epithelial to mesenchymal transition and cancer cell survival. In gastric tumors, the HIF1 regulated genes were observed to express in diffuse, poorly differentiated and stage-3 tumors. The analyses reveal i) activation of HIF1 in a sub-set of gastric tumors, ii) the pathways associated with the HIF1 activation in gastric tumors, and iii) genes involved in HIF1 mediated transcription in gastric cancer. We are further investigating the drugs that would best suit for this sub-set of tumors with activated HIF1.