Regulator of G protein signaling 16 restrains apoptosis in colorectal cancer through disrupting TRAF6-TAB2-TAK1-JNK/p38 MAPK signaling.

Colorectal cancer (CRC) remains a major global cause of cancer-related mortality, lacking effective biomarkers and therapeutic targets. Revealing the critical pathogenic factors of CRC and the underlying mechanisms would offer potential therapeutic strategies for clinical application. G protein signaling (RGS) protein family modulators play essential role within regulating downstream signaling of GPCR receptors, with function in cancers unclear. Our study focused on the expression patterns of RGS proteins in CRC, identifying Regulator of G protein signaling 16 (RGS16) as a prospective diagnostic and therapeutic target. Analyzing 899 CRC tissues revealed elevated RGS16 levels, correlating with clinicopathological features and CRC prognosis by immunohistochemistry (IHC) combined with microarray. We confirmed the elevated RGS16 protein level in CRC, and found that patients with RGS16-high tumors exhibited decreased disease-specific survival (DSS) and disease-free survival (DFS) compared to those with low RGS16 expression. Functional assays demonstrated that RGS16 promoted the CRC progression, knockdown of RGS16 led to significantly increased apoptosis rates of CRC in vitro and in vivo. Notably, we also confirmed these phenotypes of RGS16 in organoids originated from resected primary human CRC tissues. Mechanistically, RGS16 restrained JNK/P38-mediated apoptosis in CRC cells through disrupting the recruitment of TAB2/TAK1 to TRAF6. This study provides insights into addressing the challenges posed by CRC, offering avenues for clinical translation.

USP37 promotes angiogenesis and metastasis in colorectal cancer by facilitating ß-catenin stability.

Ubiquitin-specific peptidase 37 (USP37) is a novel deubiquitinating enzyme, which has been found to be involved in the progression of multiple tumors. However, its function in colorectal cancer (CRC) remains unclear. Here, we firstly proved that USP37 was up-regulated in CRC cases, and high USP37 expression predicted poor survival of CRC cases. USP37 up-regulation promoted the proliferation, cell cycle progression, apoptosis inhibition, migration, invasion, epithelial mesenchymal transition (EMT) and stemness of CRC cells; moreover, USP37 facilitated the angiogenesis of human umbilical vein endothelial cells (HUVECs). However, USP37 silencing showed the opposite function. In vivo experiment suggested that USP37 silencing suppressed the growth and lung metastasis of CRC in nude mice. Interestingly, we found that CTNNB1 (gene coding for ß-catenin) level was positively correlated with USP37 level in CRC and USP37 silencing suppressed the expression of ß-catenin in CRC cells and xenograft tumor tissues. Further mechanistic studies showed that USP37 could enhance the stability of ß-catenin by inhibiting its ubiquitination. Taken together, USP37 acts as an oncogene in CRC, which promotes angiogenesis, metastasis and stemness by enhancing ß-catenin stability via inhibiting its ubiquitination. USP37 may be a usefully target in CRC clinical treatment.

ZNF516 suppresses stem cell-like characteristics by regulating the transcription of Sox2 in colorectal cancer.

This study aimed to explore the biological function and the molecular mechanism of the action of zinc-finger protein 516 (ZNF516) in suppressing stem cell-like characteristics and tumor progression in colorectal cancer (CRC). The expression profiles of ZNF516 in clinical samples and from The Cancer Genome Atlas (TCGA) CRC database were analyzed. Cell transfection was used to overexpress and knockdown ZNF516 in CRC cells. Cell counting kit-8 (CCK8) assays, transwell assays and flow cytometry were used to study cell proliferation, invasion and stem cell-like characteristics, respectively. Cycloheximide (CHX) was used to examine the effect of ZNF516 expression on Sox2 degradation. Finally, the effects of ZNF516 on tumor growth and metastasis were tested on xenograft tumor models and lung metastasis models in immunocompromised mice. We found that the expression level of ZNF516 was lower in TCGA CRC tissue and clinical CRC samples compared with that in normal colorectal mucosal cells. Overexpression of ZNF516 in CRC cells inhibited cell proliferation, colony formation, migration and invasion, whereas ZNF516 knockdown showed the opposite effects. In addition, ZNF516 overexpression inhibited the sphere-forming ability of CRC cells and suppressed the expression of CD133, CD44 and Oct4 in CRC cells. ZNF516 decreased the stability of Sox2 through a mechanism mediated by EGFR. By in vivo experiments using mouse tumor models, we further confirmed that ZNF516 attenuated tumor growth and alleviated lung metastasis in mice. In conclusion, ZNF516 functions as a tumor suppressor by regulating the transcription of Sox2 to inhibit cell proliferation, invasion, and the development of stem cell-like characteristics in CRC cells.

An MRI-based pelvimetry nomogram for predicting surgical difficulty of transabdominal resection in patients with middle and low rectal cancer.

Objective: The current work aimed to develop a nomogram comprised of MRI-based pelvimetry and clinical factors for predicting the difficulty of rectal surgery for middle and low rectal cancer (RC). Methods: Consecutive mid to low RC cases who underwent transabdominal resection between June 2020 and August 2021 were retrospectively enrolled. Univariable and multivariable logistic regression analyses were carried out for identifying factors (clinical factors and MRI-based pelvimetry parameters) independently associated with the difficulty level of rectal surgery. A nomogram model was established with the selected parameters for predicting the probability of high surgical difficulty. The predictive ability of the nomogram model was assessed by the receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Results: A total of 122 cases were included. BMI (OR = 1.269, p = 0.006), pelvic inlet (OR = 1.057, p = 0.024) and intertuberous distance (OR = 0.938, p = 0.001) independently predicted surgical difficulty level in multivariate logistic regression analysis. The nomogram model combining these predictors had an area under the ROC curve (AUC) of 0.801 (95% CI: 0.719-0.868) for the prediction of a high level of surgical difficulty. The DCA suggested that using the nomogram to predict surgical difficulty provided a clinical benefit. Conclusions: The nomogram model is feasible for predicting the difficulty level of rectal surgery, utilizing MRI-based pelvimetry parameters and clinical factors in mid to low RC cases.