Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis

Tian, Ye; Ma, Xianghui; Lv, Cong; Sheng, Xiaole; Li, Xiang; Zhao, Ran; Song, Yongli; Andl, Thomas; Plikus, Maksim V.; Sun, Jinyue; Ren, Fazheng; Shuai, Jianwei; Lengner, Christopher J.; Cui, Wei; Yu, Zhengquan

doi:10.7554/elife.29538

Cited by 59 publications

(53 citation statements)

References 63 publications

(118 reference statements)

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“…Thus, intestinal epithelial miR‐31‐5p expression seems intrinsically linked to colonic inflammation—known to increase the risk of developing CRC. Alternatively, the poor outcome associated with high MIR31 activity may be related to the role of miR‐31‐5p in promoting stem cell expansion . MIR31 positivity may represent stem cell‐like subpopulations inherently resistant to chemotherapy, and LGR5 + positive stem cells were recently found to be critical in the formation and maintenance of CRC liver metastasis .…”

Section: Discussionmentioning

confidence: 99%

“…showed that MIR31HG , independent of the encoded miR‐31‐5p, promotes tumor development through HIF1A co‐activation . Tian and colleagues demonstrated that miR‐31‐5p acts as a “cell‐autonomous post‐transcriptional regulator of the ISC [intestinal stem cell] niche” and is induced upon tissue damage by facilitating the subsequent expansion of LGR5 + ISCs as to repopulate the intestinal lining …”

Section: Discussionmentioning

confidence: 99%

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Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

Eide

Eilertsen

Sveen

2019

Intl Journal of Cancer

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Elevated miR‐31 expression is associated with poor outcome in colorectal cancer (CRC). Whether the prognostic information is independent of known molecular subgroups and gene expression‐based consensus molecular subtypes (CMS) is currently unknown. To investigate this, we analyzed nearly 2000 CRC biopsies and preclinical models. The expression of miR‐31‐5p and its host transcript, long noncoding RNA MIR31HG , was strongly correlated (Spearman's ρ > 0.80). MIR31HG outlier expression was observed in 158/1265 (12%) of pCRCs and was associated with depletion of CMS2‐canonical subgroup (odds ratio = 0.21 [0.11–0.35]) and shorter relapse‐free survival (RFS) in multivariable analysis (adjusted hazard ratio = 2.2 [1.6–3.0]). For stage II disease, 5‐year RFS for patients with MIR31HG outlier status was 49% compared to 77% for those with normal‐like expression. MIR31HG outlier status was associated with inferior outcome also within clinical high risk groups and within the poor prognostic CMS4‐mesenchymal gene expression subtype specifically. Preclinical models with MIR31HG outlier expression were characterized by reduced expression of MYC targets as well as elevated epithelial‐mesenchymal transition, TNF‐α/NFκB, TGF‐β, and IFN‐α/γ gene expression signatures, indicating cancer cell‐intrinsic properties resembling the CMS4 subgroup—associations which were recapitulated in patient biopsies. Moreover, the prognostic value of MIR31HG outlier status was independent of cytotoxic T lymphocyte and fibroblast infiltration. We here present evidence that MIR31HG expression provides clinical stratification beyond major gene expression phenotypes and tumor immune and stromal cell infiltration and propose a model where increased expression is an indicator of a cellular state conferring intrinsic invasive and/or immuno‐evasive capabilities.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

Eide

Eilertsen

Sveen

2019

Intl Journal of Cancer

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“…Using combinational computational methods to predict miR-31 target-pathways, one group found a connection specifically between miR-31 and tight junctions in lung epithelium (36). Most recently, Yu et al demonstrated using in vivo knock-in and knock-out models that miR-31 plays a role in regulating intestinal stem cell behavior during regeneration after radiation injury (37). We show that patient cryptderived colonoids in a sterile environment retain the aberration in miR-31 expression present in the tissue of origin, which supports a cellular defect that is intrinsic and not secondary to inflammation or other external signals due to the presence of disease.…”

Section: Discussionmentioning

confidence: 99%

Colonic Epithelial miR-31 Associates with the Development of Crohn’s Phenotypes

Keith

Barrow

Kazgan

et al. 2018

Preprint

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Crohn’s disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity. In this study, small RNA-sequencing and microRNA profiling in the colon revealed two distinct molecular subtypes, each with different clinical associations, in both adult and treatment-naïve pediatric CD patients. Notably, we found that microRNA-31 (miR-31) expression by itself can stratify patients into these two subtypes. Through detailed analysis of several colonic mucosa cell types from adult patients, we found that differential levels of miR-31 are particularly pronounced in epithelial cells. We generated patient crypt-derived epithelial colonoids and showed that miR-31 expression differences preserved in this ex-vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery are associated with post-operative recurrence of ileal disease. In pediatric patients, lower miR-31 expression at the time of diagnosis is associated with the future development of fibrostenotic ileal CD requiring surgery. These findings represent an important step forward in designing more effective clinical trials and developing personalized therapies for CD.

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“…However, in CRC cells, LOC554202 has a tumor suppressor role in the activation of specific caspase cleavage cascades, and low expression of LOC554202 was associated with advanced pathologic stage and increased tumor size (32). miR-31 is a widely investigated miRNA and studies have reported controversial conclusions regarding its role in CRC cells (52)(53)(54)(55)(56). These studies suggest that a high expression of this miRNA in cancer does not always result in a decreased tumor growth, including that noted in cases of the oncosuppressors p53 and phosphatase and tensin homolog.…”

Section: Os ---------------------------------------------------------mentioning

confidence: 99%

High expression of microRNA‑31 and its host gene LOC554202 predict favorable outcomes in patients with colorectal cancer treated with oxaliplatin

Xin

et al. 2018

Oncol Rep

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The expression levels of microRNA‑31 (miR‑31) and LOC554202 have been previously investigated in colorectal cancer (CRC) and their oncogenic and/or tumor suppressive roles have been described. The aim of the present study was to examine the role of miR‑31 and its host gene LOC554202 in the prognosis of patients with CRC. Patients with CRC treated with oxaliplatin‑based chemotherapy between June 2005 and March 2010 were recruited to the First Affiliated Hospital of China Medical University. Tumor and adjacent mucosal tissues were collected. The detection of miR‑31 and/or LOC554202 was performed with probe hybridization targeting. Correlation analysis was performed among the expression levels of miR‑31, LOC554202, and their association with clinicopathological parameters and/or survival rates. miR‑31 and LOC554202 were expressed at high levels in CRC (P<0.01) compared with adjacent intestinal mucosa. A linear correlation was noted for the two markers in CRC tissues (P<0.01). The expression of miR‑31 was significantly higher in adenocarcinoma than in the adjacent intestinal mucosa (P<0.01), whereas the expression of LOC554202 was significantly higher in the adenocarcinoma and the rectal cancer tissue regions (P<0.01). The high expression levels of miR‑31 and LOC554202 were associated with high disease‑free survival (DFS) and overall survival (OS) rates (P<0.05). Associations between the increase in DFS and OS and the elevated expression levels of miR‑31 and LOC554202 were present in patients with colon cancer but not in patients with rectal cancer (P<0.05). These data indicated that miR‑31 and LOC554202 may be potential markers for evaluation of the prognosis of patients treated with oxaliplatin‑based chemotherapy.

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Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis

Cited by 59 publications

References 63 publications

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

Colonic Epithelial miR-31 Associates with the Development of Crohn’s Phenotypes

High expression of microRNA‑31 and its host gene LOC554202 predict favorable outcomes in patients with colorectal cancer treated with oxaliplatin

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