The molecular pathogenesis of colorectal cancer (CRC) has been widely investigated in recent years. Accumulating evidence has indicated that microRNA (miRNA) dysregulation participates in the processes of driving CRC initiation and progression. Aberrant expression of miR-1301 has been found in various tumor types. However, its role in CRC remains to be elucidated. In the present study, we identified miR-1301 was enriched in normal colorectal tissues and significantly downregulated in CRC. Decreased level of miR-1301 strongly correlated with aggressive pathological characteristics, including advanced stage and metastasis. Bioinformatics and dual luciferase assay demonstrated that STAT3 is a direct target of miR-1301. Gain and loss-of-function assays showed that miR-1301 had no effect on cell proliferation. Overexpression of miR-1301 suppressed cell migration and invasion capacity of pSTAT3-positive LoVo cells, but not pSTAT3-negative SW480 cells, while inhibition of miR-1301 consistently promoted cell migration and invasion in both cell lines. Additionally, miR-1301 inhibition restored the suppressed migration and invasion of STAT3-knockdown LoVo cells. MiR-1301 functioned as a tumor suppressor to modulate the IL6/STAT3 signaling pathway. In summary, this study highlights the significant role of miR-1301/STAT3 axis in CRC metastasis.

Aberrant loss of tumor-suppressor genes plays a crucial role in tumorigenesis and development of colorectal cancer (CRC). Extensive studies have reported tha hypermethylation of Ras association domain family member 6 (RASSF6) is common in various solid tumors. Another important mode of epigenetic regulation, microRNA (miRNA) regulation of RASSF6, is far from clear. The aim of the present work was to screen out novel miRNA regulating RASSF6, and to explore its underlying mechanism in CRC. With the use of bioinformatics, clinical sample data, and luciferase binding assay, we determined that microRNA-496 (miR-496) could be a novel oncomiR that directly binds to RASSF6. Next, a series of miR-496 mimics or inhibitor, or RASSF6 small interfering RNA (siRNA) introduced into CRC cells were applied to examine the effect of miR-496 on CRC cell viability, migration, and epithelial-mesenchymal transition (EMT). The results demonstrated that miR-496/RASSF6 could promote cell migration and EMT via Wnt signaling activation, but had no effect on cell viability. Our results confirmed that the miR-496/RASSF6 axis is involved in Wnt pathway-mediated tumor metastasis, highlighting its potential as a therapeutic target for CRC.

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Accumulation of varieties of epigenetic changes, including miRNA regulation, is one of the fundamental processes driving CRC initiation and progression. Mir-92a has been reported in several studies as an oncogene, and particularly in colorectal cancer, it has become a useful biomarker for early detection of CRC in both serum or stool. The Cancer Genome Atlas (TCGA) is a powerful database to analyze cancer-related genes and their correlation with patients' pathological information. However, miR-92a expression and its regulating target genes has yet to be investigated in TCGA system. In this study, we found miR-92a expression is associated with CRC pathological process. Notably, high expression of miR-92a mainly occurs in microsatellite-stable (MSS) cases. Further experiments showed exogenous introduction of miR-92a into LoVo and SW480 cells could enhance cell proliferation, migration, and invasion, whereas inhibition of miR-92a showed the opposite effects. A system analysis based on binding capacity and expression correlation analysis confirmed DKK3 and KLF4 are the top target genes of miR-92a, and novel target SMAD7 highlights the role of miR-92a in BMPs/SMAD pathway. In conclusion, miR-92a acts as an oncomir and directly targets Wnt/β-catenin, PTEN/Akt/FoxO, and BMP/Smads related genes, thus participates in CRC progression.

Background Although the genetic spectrum of human colorectal cancer (CRC) is mainly characterized by APC , KRAS and TP53 mutations, driver genes in tumor initiation have not been conclusively demonstrated. In this study, we aimed to identify novel markers for CRC. Methods We performed exome analysis of sporadic colorectal cancer (sCRC) coding regions to screen loss of function (LoF) mutation genes, and carried out systems-level approaches to confirm top rank gene in this study. Results We identified loss of BMP5 is an early event in CRC . Deep sequencing identified BMP5 was mutated in 7.7% (8/104) of sCRC samples, with 37.5% truncating mutation frequency. Notably, BMP5 negative expression and its prognostic value is uniquely significant in sCRC but not in other tumor types. Furthermore, BMP5 expression was positively correlated with E-cadherin in CRC patients and its dysregulation play a vital role in epithelial-mesenchymal transition (EMT), thus triggering tumor initiation and development. RNA sequencing identified, independent of BMP/Smads pathway, BMP5 signaled though Jak-Stat pathways to inhibit the activation of oncogene EPSTI1 . Conclusions Our result support a novel concept that the importance of BMP5 in sCRC. The tumor suppressor role of BMP5 highlights its crucial role in CRC initiation and development.

MiRNA regulation is a crucial way of epigenetic changes. Mir-32 has been reported in several studies as an oncogene, however, its role and target in colorectal cancer (CRC) remains unclear. In this study, we aimed to explore the role of miR-32 in CRC using bioinformatic analysis and functional assays. We collected 28 pairs of CRC tumor tissues and adjacent normal tissues and confirmed miR-32 was significantly upregulated in CRC. Expression and clinical data from The Cancer Genome Atlas (TCGA) identified miR-32 expression is associated with CRC lymphatic invasion, metastasis, and correlates with patients' poor survival. Functional studies demonstrated that overexpression of miR-32 in LoVo cells promoted cell proliferation and migration, whereas inhibition of miR-32 in HCT 116 cells showed the opposite results. Using bioinformatics, we identified Bone morphogenetic protein 5 (BMP5) is a direct target of miR-32, and loss of tumor suppressor BMP5 may partially due to the miR-32 dysregulation. The inverse correlation between miR-32 and BMP5 was observed in CRC, especially in advanced tumor patients. Moreover, cotransfection of miR-32 mimics and BMP5 recombinant vector in LoVo cells demonstrated that BMP5 could reverse the oncomir effect of miR-32. Taken together, our results suggested a significant role of miR-32/BMP5 axis in CRC tumorigenesis.