MiR-205 and MiR-373 Are Associated with Aggressive Human Mucinous Colorectal Cancer

Abstract

Mucinous adenocarcinoma (MAC) represents a distinct histopathological entity of colorectal cancer (CRC), which is associated with disease progression and poor prognosis. Here, we found that expression levels of miR-205 and miR-373 were specifically upregulated only in patients with mucinous colon cancers, but not in CRC that lack mucinous components. To investigate the effects of miR-205 and miR-373 on intestinal epithelial cell (IEC) biology by gain- and loss-of-function experiments in a proof-of-concept approach, we chose previously established in-vitro human Caco-2-based models of differentiated, non-invasive (expressing TLR4 wild-type; termed Caco-2[WT]) versus undifferentiated, invasive (expressing TLR4 mutant D299G; termed Caco-2[D299G]) IEC. Enterocyte-like Caco-2[WT] showed low levels of miR-205 and miR-373 expression, while both miRNAs were significantly upregulated in colorectal carcinoma-like Caco-2[D299G], thus resembling the miRNA expression pattern of paired normal versus tumor samples from MAC patients. Using stable transfection, we generated miR-205- or miR-373-expressing and miR-205- or miR-373-inhibiting subclones of these IEC lines. We found that introduction of miR-205 into Caco-2[WT] led to expansion of mucus-secreting goblet cell-like cells, which was associated with induction of KLF4, MUC2 and TGFβ1 expression. Activation of miR-205 in Caco-2[WT] induced chemoresistance, while inhibition of miR-205 in Caco-2[D299G] promoted chemosensitivity. Caco-2[WT] overexpressing miR-373 showed mitotic abnormalities and underwent morphologic changes (loss of epithelial polarity, cytoskeletal reorganization, and junctional disruption) associated with epithelial-mesenchymal transition and progression to inflammation-associated colonic carcinoma, which correlated with induction of phosphorylated STAT3 and N-CADHERIN expression. Functionally, introduction of miR-373 into Caco-2[WT] mediated loss of cell-cell adhesion and increased proliferation and invasion. Reversely, inhibition of miR-373 allowed mesenchymal IEC to regain epithelial properties, which correlated with absence of neoplastic progression. Using xenografts in mice demonstrated miR-373-mediated acceleration of malignant intestinal tumor growth. In conclusion, our results provide first evidence that miR-205 and miR-373 may differentially contribute to the aggressive phenotype of MAC in CRC.

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

“…S2 Table shows the histopathological features of the 54 patients. Of note, our patients with CAC showed a less advanced tumor stage distribution with rarer metastasis than patients with CRC at the time of diagnosis, because all UC patients underwent increased endoscopic surveillance and tumor lesions were therefore detected at an earlier stage than in the non-UC population, as previously described [29]. This study (anonymous analysis of historical collection) abided by the Declaration of Helsinki and was approved by the local Ethics Committee of the Medical Faculty of the University Duisburg-Essen, Germany (“Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen”; permit #13-5602-BO).…”

Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance

“…In essence, over 10% of all reported research findings of miRNA influences in cancer chemoresistance demonstrated that such a phenotype modulation was effected through simultaneous dysregulation of multiple miRNAs, rather than an individual putative chemoresistance miRNA—though no specific miRNA combination was identified as most prevalent by the authors [44,46,47,48,49,62,67,71,76,81,85,88,132,133,158,168,201,203,211,212,213,217,223,224,228,230]. This suggests that miRNA influences on cellular functions also occur at a more complex level, whereby it is a signature dysregulated expression pattern of two (or more) miRNAs that trigger simultaneous downregulation of a specific set of target transcripts leading to an ultimate change in cellular/tissue phenotype.…”

MicroRNA‑373 promotes cell migration via targeting salt‑inducible kinase 1 expression in melanoma

“…In parallel, miR-373 inhibited ovarian cancer cell invasion and metastasis by targeting RAB22A (24). On the other hand, miR-373 was associated with aggressive human mucinous colorectal cancer (25). Upregulated miR-373 promoted cell migration in breast cancer through epigenetic silencing of integrin subunit α-2 (26).…”