CTRP6, a novel metabolic / immunomodulator that binds to multiple endogenous ligands, is an intermediate link in obesity with adipose tissue inflammation and insulin resistance[22-23].CTRP6 has a role in regulating the secretion of inflammatory factors and may have proinflammatory or inhibitory inflammatory effects depending on the site of action.It was shown that knockdown of CTRP6 resulted in a significant reduction in the production levels of tumor necrosis factor(TNF)-α, interleukin (IL) -1, and IL-6 in high glucose-induced glomerular mesilial cells[24].Overexpression of CTRP6 can activate PI3K/Akt signaling by inhibiting the rhoa/rock/PTen pathway and improve the inflammatory damage caused by cerebral ischemia / reperfusion[25].
Activation of the PI3K/Akt pathway is one of the common molecular mechanisms in human tumor development.PI3K/Akt signaling negatively regulates processes like cell growth, proliferation, glucose metabolism, and migration, and is thought to play a key regulatory role in tumor invasiveness[26].One of the specific mechanisms by which the PI3K/Akt pathway promotes tumorigenesis is the dysregulation of inflammatory mediators and immunity.It has been shown that rosemary acid subsequently prevents lung tumor invasion by reducing the production of inflammatory factors, such as IL-6, IL-8, TNF-α and COX-2, by inhibiting Akt phosphorylation[27].We speculate that this mechanism of action of the PI3K/Akt pathway is equally applicable during the pathogenesis of digestive tumors.Recent studies show that the chronic inflammatory status due to obesity is a risk factor for the development of colorectal cancer, and that the PI3K/Akt pathway is one of the important pathways to mediate this process[28].The PI3K/Akt pathway also mediates the aggressive role of cancer-associated fibroblasts in gastric cancer, while IL-8 enhanced expression of PI3K/Akt pathway expression and increased chemoresistance to gastric cancer[29-30].In the study of hepatoma, royal plasma produced increased IL-2 levels and TNF-αcontent in serum by inhibiting PI3K expression and phosphorylation of AKT, thereby preventing and controlling hepatocarcinogenesis in mice[31].From the above studies, we can speculate that CTRP6 may promote tumorigenesis and progression in the digestive system by releasing inflammatory factors by activating the PI3K/Akt pathway.Results provide strong evidence for the above speculation in Wan et al[6] by inhibiting CTRP6 to block AKT signaling and in turn preventing the survival and migration of hepatocellular carcinoma.
It was previously shown that overexpressed CTRP6 enhances the proliferation, migration and invasion of lung adenocarcinoma cells by regulating the signaling pathway in which MAPK lies[3].The MAPK/NF-kB pathway is one of the common intersection pathways of various cellular signaling pathways, such as inflammation, stress, and is involved in cellular activity, including carcinogenesis[32].Activation of MAPK/NF-kB signaling enhances the secretion of IL-1β and IL-18 and leading to the development of renal inflammation[33].The study by Eyre et al[34] found that the globular domain of CTRP6 can stimulate the phosphorylation of MAPK/ERK1/2, and when treated with selective MAPK/ERK1/2 inhibitors, it will eliminate CTRP6-mediated IL-10 expression.The latest study reveal the fact that digestive tract tumors are regulated by inflammatory factor secretion by the MAPK signaling pathway.IL-1β, IL-6 and TNF-α, the inflammatory factors produced by inhibiting the MAPK pathway, can effectively delay the progression in colorectal cancer[35].In gastric cancer, IL-6 promotes the growth and metastasis of gastric cancer, and resveratrol can prevent IL-6-induced gastric cancer metastasis by blocking Raf/MAPK signaling[36].Pepperine in turn inhibits IL-1β -induced IL-6 expression by inhibiting the MAPK and STAT3 pathways in gastric cancer cells[37].Other recent studies have also demonstrated the oncogenic role of inflammatory factors such as IL-1β and IL-6 in gastric cancer, colorectal cancer, and liver cancer[38、39、40、41].We believe that CTRP6 activation of the MAPK/ERK1/2/NF-kB pathway promotes the secretion of inflammatory factors such as IL-1β, IL-6 and TNF-α and in turn accelerates tumor progression.
In conclusion, it can be speculated that one role of CTRP6 in digestive system tumors is to regulate tumor development and development through the activation of the Akt pathway and regulating inflammatory factors in the MAPK pathway (Figure 1).