microRNA-135b promotes cancer progression acting as a downstream effector of oncogenic pathways in colon cancer

Abstract

SUMMARYMicroRNA deregulation is frequent in human colorectal cancers (CRCs), but little is known as to whether it represents a bystander event or actually drives tumor progression in vivo. We show that miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression. We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downsteam effector of oncogenic pathways and a potential target for CRC treatment.

Upregulation of microRNA‐135b and microRNA‐182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3K/AKT pathway

“…MiR‐149 has been identified to be correlated with the metastasis and drug resistance to 5‐FU in CRC, and miR‐139‐5p sensitized CRC cell lines to 5‐FU treatment . Additionally, inhibition of miR‐135b in CRC mouse model reduced proliferation, invasion and apoptosis, and miR‐135b suppressed the ability of PTEN in CRC . MiR‐182 functioned as a key microRNA to promote cell proliferation, metastasis, and drug resistance in cancers according to recent studies .…”

miR-135b- and miR-146b-dependent silencing of calcium-sensing receptor expression in colorectal tumors

“…Several studies have reported upregulation of miR‐135b amongst several other microRNAs in colorectal tumor tissues compared with normal colonic tissue, and this was associated with increased tumor invasiveness and migration . Upregulation of miR‐135b is observed in early stages of human CRC tumorigenesis, as well as in mouse models, in tumors originating from chronically inflamed colon or caused by mutations of the adenomatous polyposis coli (APC) gene . Elevated levels of miR‐135b in colorectal tumors have been associated with several pathways, such as the Wnt pathway and the PI3K/PTEN pathway (phosphoinositide 3‐kinase/phosphatase and tensin homolog) .…”

“…Upregulation of miR‐135b is observed in early stages of human CRC tumorigenesis, as well as in mouse models, in tumors originating from chronically inflamed colon or caused by mutations of the adenomatous polyposis coli (APC) gene . Elevated levels of miR‐135b in colorectal tumors have been associated with several pathways, such as the Wnt pathway and the PI3K/PTEN pathway (phosphoinositide 3‐kinase/phosphatase and tensin homolog) . miR‐135b suppressed expression of APC, transforming growth factor β (TGFβ) and TGFβ receptor II, and of death‐associated protein kinase 1, indicating its important role during malignant transformation of colonic epithelial cells .…”

“…Elevated levels of miR‐135b in colorectal tumors have been associated with several pathways, such as the Wnt pathway and the PI3K/PTEN pathway (phosphoinositide 3‐kinase/phosphatase and tensin homolog) . miR‐135b suppressed expression of APC, transforming growth factor β (TGFβ) and TGFβ receptor II, and of death‐associated protein kinase 1, indicating its important role during malignant transformation of colonic epithelial cells . A recent study showed that in CRC cell lines TGFβ signaling was dependent on CaSR expression .…”

What is the Potential of Epigenetics in Drug Development?

“…For instance, miRNA-135b upregulation is common in sporadic and inflammatory bowel disease-associated human colorectal cancer (CRC), which correlates with tumor stage and poor clinical outcome [9]. For instance, miRNA-135b upregulation is common in sporadic and inflammatory bowel disease-associated human colorectal cancer (CRC), which correlates with tumor stage and poor clinical outcome [9].…”