The primary consequence of PI3K activation is to catalyze the conversion of membrane-bound PIP2 to PIP3. As a second messenger, PIP3 works as a ligand to recruit PH domaincontaining proteins ) to the inner surface of cell membrane. Once positioned at the cell membrane, Akt1 is activated by PDK1 through the phosphorylation of threonine 308, which is in the activation loop of Akt. The full repertoire of Akt functions is then accessible when it undergoes phosphorylation at serine 473. Once activated, Akt is poised to serve as a central node for regulating a variety of cellular functions, including but not limited to proliferation, cell survival, metabolism, and angiogenesis. Recent studies have shown that the PI3K/Akt signaling pathway is aberrantly activated in many cancer types, including CRC and that the activation of PI3K signaling promotes cancer HhAntag691 formation through a variety of mechanisms, including the induction of cell proliferation, migration and cancer cell survival. In this study, we found that CCR6 enhanced the aggressiveness of CRC cells partly through PI3K activation. To further elucidate the downstream signaling pathway involving upregulated CCR6 in CRC aggressiveness, we compared mRNA expression profiles between HCT116CCR6 and HCT116Ctr cells using a human tumor metastasis real-time PCR array containing 84 genes known to be involved in metastasis. Genes selected for this array encode several classes of protein factors including cell adhesion, ECM components, cell cycle, cell growth and proliferation, apoptosis, transcription factors and regulators, and other genes related to tumor metastasis. These genes can mimic all aspects of the metastatic development. Among the 84 genes, we identified 5 genes with different expression. FXYD5 overexpression in pancreatic ductal adenocarcinoma reflects tumor aggressiveness and promotes metastasis. Syk has been shown to mediate chemomigration in nasopharyngeal carcinoma cells. The down-regulation of E-cadherin is considered as a critical event for the invasion and metastasis of colorectal carcinoma, and the loss of Ecadherin-mediated cell adhesion is one rate-limiting step in the progression from adenoma to carcinoma. KISS1 is a gene that suppresses the metastasis of tumor cells without affecting tumorigenicity. The proteins encoded by the TIMP2 gene family are natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in the degradation of the extracellular matrix. Our data suggest that overexpressed CCR6 likely upregulated metastasis genes and downregulated metastasis suppressor genes to enhance the aggressiveness of HCT116CCR6 cells. To date, there are no small molecule programs in clinical development for anti-CCR6 therapy for CRC treatment. In this study, we demonstrated that targeting the CCR6 in the tumor cell or the tumor microenvironment inhibited CRC progression in mice. Thus, our findings highlight CCR6 as a promising therapeutic target for CRC. In addition, we have shown that upregulated CCR6 enhanced CRC cell proliferation, migration and in vivo tumor metastasis, likely by altering the expression of tumor metastasis-related genes.