• Intestinal injury
• Intestinal regeneration
• Intestinal stem cells
• Iron

• GZC20230779 the Postdoctoral Fellowship Program of the China Postdoctoral Science Foundation
• 2024JJ6310 the Natural Science Foundation of Hunan Province
• No. 32130099 National Natural Science Foundation of China
• ISA2020113 Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process open fund projects

• Smad
• cancer stem cell
• carcinogenesis
• colitis-associated colorectal cancer
• mouse model

• 16K09330 Japan Society for the Promotion of Science
• 25460938 Japan Society for the Promotion of Science
• 22K08020 Japan Society for the Promotion of Science
• a research grant Kyoto Health Management Research Foundation

• Cell proliferation
• Docetaxel
• Prostate cancer
• Smad3
• Tumor glycolysis

• Biomarkers
• Cancer stem cells
• Carcinogenesis
• Esophageal neoplasms
• Stem cells

• Smad
• cancer stem cell
• colitis-associated colorectal cancer
• epithelial-mesenchymal transition
• metastasis
• mouse model

Intestinal regeneration and tumorigenesis are believed to be driven by intestinal stem cells (ISCs). Elucidating mechanisms underlying ISC activation during regeneration and tumorigenesis can help uncover the underlying principles of intestinal homeostasis and disease including colorectal cancer. Here we show that miR-31 drives ISC proliferation, and protects ISCs against apoptosis, both during homeostasis and regeneration in response to ionizing radiation injury. Furthermore, miR-31 has oncogenic properties, promoting intestinal tumorigenesis. Mechanistically, miR-31 acts to balance input from Wnt, BMP, TGFβ signals to coordinate control of intestinal homeostasis, regeneration and tumorigenesis. We further find that miR-31 is regulated by the STAT3 signaling pathway in response to radiation injury. These findings identify miR-31 as a critical modulator of ISC biology, and a potential therapeutic target for a broad range of intestinal regenerative disorders and cancers.

Cells lining the inner wall of the gut help to absorb nutrients and to protect the body against harmful microbes and substances. Being on the front line of defense means that these cells often sustain injuries. Specialized cells called intestinal stem cells keep the tissues healthy by replacing the damaged and dying cells.

The intestinal stem cells can produce copies of themselves and generate precursors of the gut cells. They also have specific mechanism to protect themselves from cell death. These processes are regulated by different signals that are generated by the cell themselves or the neighboring cells. If these processes get out of control, cells can easily be depleted or develop into cancer cells. Until now, it remained unclear how intestinal stem cells can differentiate between and respond to multiple and simultaneous signals.

It is known that short RNA molecules called microRNA play an important role in the signaling pathways of damaged cells and during cancer development. In the gut, different microRNAs, including microRNA-31,help to keep the gut lining intact. However, previous research has shown that bowel cancer cells also contain high amounts of microRNA-31.

To see whether microRNA-31 plays a role in controlling the signaling systems in intestinal stem cells, Tian, Ma, Lv et al. looked at genetically modified mice that either had too much microRNA-31 or none. Mice with too much microRNA-31 produced more intestinal stem cells and were able to better repair any cell damage. Mice without microRNA-31 gave rise to fewer intestinal stem cellsand had no damage repair, but were able to stop cancer cells in the gut from growing.

The results showed that microRNA-31 in intestinal stem cells helps the cells to divide and to protect themselves from cell death. It controlled and balanced the different types of cell signaling by either repressing or activating various signals. When Tian et al. damaged the stem cells using radiation, the cells increased their microRNA-31 levels as a defense mechanism. This helped the cells to survive and to activate repair mechanisms. Furthermore, Tian et al. discovered that microRNA-31 can enhance the growth of tumors.

These results indicate that microRNA-31 plays an important role both in repairing gut linings and furthering tumor development. A next step will be to see whether cancer cells use microRNA-31 to protect themselves from chemo- and radiation therapy. This could help scientists find new ways to render cancerous cells more susceptible to existing cancer therapies.

• BMP
• Wnt
• colorectal cancer
• developmental biology
• intestinal stem cell
• miR-31
• mouse
• regeneration
• stem cells

Aberrant expression of microRNA (miR)-1 has been observed in many human malignancies. However, the function and underlying mechanism of miR-1 remains elusive. To address the specific role of miR-1 in tumor glycolysis using the gain- or loss-of-function studies. Metabolic studies combined with gene expression analysis were performed in vitro and in vivo. We demonstrated aberrant expression of miR-1 in aerobic glycolysis, the Warburg effect, in cancer cells. MiR-1 suppressed aerobic glycolysis and tumor cell proliferation via inactivation of Smad3 and targeting HIF-1α, leading to reduce HK2 and MCT4 expression, which illustrated a novel pathway to mediate aerobic glycolysis in cancer cells. Overexpression of miR-1 mimics significantly decreased tumor glycolysis, including lactate production and glucose uptake, and cell proliferation, and these effects were reversed by ectopic expression of Smad3. Importantly, endogenous Smad3 regulated and interacted with HIF-1α, resulting in increasing activity of Smad3, and this interaction was dramatically abolished by addition of miR-1. We further demonstrated that Smad3 was central to the effects of miR-1 in colorectal cancer cells, establishing a previously unappreciated mechanism by which the miR-1/Smad3/HIF-1α axis facilitates the Warburg effect to promote cancer progression in vitro and in vivo. The results indicate that miR-1 may have an essential role as a tumor suppressor, suggesting its potential role in molecular therapy of patients with advanced colorectal cancer.

• Longevity
• Psoriasis
• Quiescence
• Squamous epithelia
• Stem cells
• Transforming growth factor beta

Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate linker regions connecting Mad homology domains, act as the intracellular mediators of the TGF-β signal transduction pathway. As the TGF-β receptors, c-Jun N-terminal kinase and cyclin-dependent kinase, differentially phosphorylate Smad2/3, we have generated numerous antibodies against linker (L) and C-terminal (C) phosphorylation sites in Smad2/3 and identified four types of phosphorylated forms: cytostatic COOH-terminally-phosphorylated Smad3 (pSmad3C), mitogenic pSmad3L (Ser-213) signaling, fibrogenic pSmad2L (Ser-245/250/255)/C signaling and migratory pSmad2/3L (Thr-220/179)/C signaling. After acute liver injury, TGF-β upregulates pSmad3C signaling and terminates pSmad3L (Ser-213)-mediated hepatocyte proliferation. TGF-β and pro-inflammatory cytokines cooperatively enhance collagen synthesis by upregulating pSmad2L (Thr-220)/C and pSmad3L (Thr-179)/C pathways in activated hepatic stellate cells. During chronic liver injuries, hepatocytes persistently affected by TGF-β and pro-inflammatory cytokines eventually become pre-neoplastic hepatocytes. Both myofibroblasts and pre-neoplastic hepatocyte exhibit the same carcinogenic (mitogenic) pSmad3L (Ser-213) and fibrogenic pSmad2L (Ser-245/250/255)/C signaling, with acquisition of fibro-carcinogenic properties and increasing risk of hepatocellular carcinoma (HCC). Firstly, we review phospho-Smad-isoform signalings in epithelial and mesenchymal cells in physiological and pathological conditions and then consider Smad linker phosphorylation as a potential target for pathological EMT during human fibro-carcinogenesis, because human Smad phospho-isoform signals can reverse from fibro-carcinogenesis to tumor-suppression in a process of MET after therapy.

• Smad
• epithelial-mesenchymal transition (EMT)
• hepatic stellate cells (HSC)
• liver fibro-carcinogenesis
• myofibroblast (MFB)
• transforming growth factor-β (TGF-β)

• Mouse model
• Smad
• cancer stem cell
• carcinogenesis
• colitis-associated colorectal cancer
• phosphorylation