Olfactomedin 4 is a key regulator of colon cancer progression

结直肠癌和结肠炎相关癌症是与炎症性肠病（IBD）相关的结直肠癌的一种亚型，是主要的健康风险和主要死亡原因。结肠癌的发生通常被认为是由一些癌基因的顺序突变和肿瘤抑制的多个阶段组成的。结直肠癌发生最常见的起始事件是大肠腺瘤性息肉病（APC）基因突变，导致Wnt/&#946；-catenin通路激活。确定APC丢失后调节肿瘤发生的分子事件对于理解结肠癌发生机制和治疗发展具有重要意义。Wnt信号通过-catenin在调节正常隐窝细胞稳态中至关重要，并在结肠癌发生中失调。几乎所有结直肠癌都表现出APC或&#946；-catenin突变，导致GSK-3磷酸化被阻断，导致&#946；-catenin稳定和Wnt/&#946；-catenin信号通路增强。在肿瘤发生过程中，通常会获得额外的突变（如KRAS和TP53）。人们早就认识到慢性IBD会增加结直肠癌的风险。转录因子NF-&#954；B也被证明是将炎症和免疫与癌症的发生和进展联系起来的关键因素。最近的一项研究表明，NF-&#954；B可以增强Wnt信号，导致上皮非干细胞去分化为肿瘤启动细胞。然而，明确Wnt信号的调控机制及其在结肠癌发生中的作用仍然是一个挑战。

Colorectal cancer and colitis-associated cancer, a subtype of colorectal cancer associated with inflammatory bowel disease (IBD), are major health risks and leading causes of death. Colon carcinogenesis is generally regarded as being composed of multiple stages of sequential mutations of some oncogenes and tumor suppress. The most common initiating event of colorectal carcinogenesis is mutation of the adenomatous polyposis coli (APC) gene, which leads to activation of the Wnt/β-catenin pathway. Identification of molecular events that regulate tumorigenesis after APC loss is important for understanding the mechanism of colon carcinogenesis and therapeutic development. Wnt signaling via β-catenin is critically important in regulating normal crypt cell homeostasis and is dysregulated in colon carcinogenesis. Almost all colorectal cancers exhibit mutation of either APC or β-catenin, which leads to the blockade of phosphorylation by GSK-3, resulting in β-catenin stabilization and enhanced Wnt/β-catenin signaling. During the course of tumorigenesis, additional mutations (such as KRAS and TP53) are usually acquired. It has long been recognized that chronic IBD increases the risk of colorectal cancer. The transcription factor NF-κB has also been shown to be a key factor linking inflammation and immunity to cancer development and progression. A recent study showed that NF-κB could enhance Wnt signaling, leading to the dedifferentiation of epithelial non-stem cells into tumor-initiating cells. However, clearly defining the regulatory mechanism of Wnt signaling and its role in colon carcinogenesis continues to present a challenge. Olfactomedin 4 (OLFM4) is an evolutionarily conserved glycoprotein that belongs to an olfactomedin family. It was first cloned in human hematopoietic myeloid cells and is also abundantly expressed in intestinal crypts. It affects a diverse set of cellular processes, including proliferation, differentiation, apoptosis, adhesion, and innate immunity against bacterial infections. OLFM4 transcription is regulated by PU.1, NF-κB, Notch, and retinoic acids. Its expression is also regulated epigenetically through promoter methylation. OLFM4 expression is upregulated in human IBD, which comprises ulcerative colitis and Crohns disease. OLFM4 interacts with NOD1 and NOD2, which are intracellular sensors for bacterial infection that have been found to be associated with Crohns disease. A recent study has demonstrated that OLFM4 is a robust marker for intestinal Lgr5-positive stem cells. OLFM4 tends to be overexpressed in early-stage colon cancer, but reduced or lost in advanced stages of the disease .These observations suggest that OLFM4 may play a role in the transition from colon adenoma to dysplastic tumors. Here we explored this possibility and found that Olfm4 deletion in ApcMin/+ mice leads to upregulation of Wnt/β-catenin signaling genes and carcinoma formation in the distal colon. We also observed that Olfm4-deficient mice exhibited robust intestinal crypt hyperplasia and severe inflammation in an azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated cancer model. In addition, we showed that OLFM4 is a both a target gene and an inhibitor of the Wnt/β-catenin pathway.