METTL16 in human diseases: What should we do next?

METTL16 is a class-I methyltransferase that is responsible for depositing a vertebrate-conserved S-adenosylmethionine site. Since 2017, there has been a growing body of research focused on METTL16, particularly in the field of structural studies. However, the role of METTL16 in cell biogenesis and human diseases has not been extensively studied, with limited understanding of its function in disease pathology. Recent studies have highlighted the complex and sometimes contradictory role that METTL16 plays in various diseases. In this work, we aim to provide a comprehensive summary of the current research on METTL16 in human diseases.

A clinical study of the correlation between metabolic-associated fatty liver disease and coronary plaque pattern.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome (MetS) and has been correlated with coronary atherosclerosis (CAS). Since NAFLD was renamed metabolic-associated fatty liver disease(MAFLD) in 2020, no studies have evaluated the correlation between MAFLD and CAS. The aim of this study was to evaluate the relationship between MAFLD and CAS. A total of 1330 patients underwent continuous coronary computed tomography angiography (CCTA) and abdominal ultrasound as part of a routine physical examination. Ultrasonography was used to assess fatty liver, and CCTA was used to assess coronary artery plaques, degree of stenosis, and diseased blood vessels. Univariate and multivariate logistic regression analyses were performed with plaque type and degree of stenosis as dependent variables and MAFLD and traditional cardiovascular risk factors as independent variables to analyze the correlation between MAFLD and CAS. Among the 1164 patients, 680 (58.4%) were diagnosed with MAFLD through a combination of ultrasound and auxiliary examinations. Compared with the non-MAFLD group, the MAFLD group had more cardiovascular risk factors,and the MAFLD group had more likely to have coronary atherosclerosis, coronary stenosis and multiple coronary artery stenosis.In the univariate logistic regression, MAFLD was significantly correlated with overall plaque, calcified plaques, noncalcified plaques, mixed plaques,and significant stenosis in the coronary arteries.(p < 0.05). After adjusting for cardiovascular risk factors , MAFLD was correlated with noncalcified plaques (1.67; 95% confidence interval (CI) 1.15-2.43; p = 0.007) and mixed plaques (1.54; 95% CI 1.10-2.16; p = 0.011). In this study, MAFLD group had more cardiovascular risk factors, MAFLD was correlated with coronary atherosclerosis,and significant stenosis.Further study found independent associations between MAFLD and noncalcified plaques and mixed plaques, which suggest a clinically relevant link between MAFLD and coronary atherosclerosis.

miR-338-3p regulates the proliferation, apoptosis and migration of SW480 cells by targeting MACC1.

The mortality and incidence rates of colorectal cancer (CRC) vary widely worldwide. miR-338-3p inhibits tumor cell proliferation in several types of cancer, however, the role of miR-338-3p on CRC remains unknown. The aim of the current study was to investigate the cellular function of miRNA-338-3p (miR-338-3p) in CRC, the malignant behavior of CRC cells and the interaction between miR-338-3p and metastasis-associated in colon cancer-1 (MACC1). miR-338-3p expression was significantly decreased in CRC tissue compared with adjacent normal tissue. In the CRC cell line SW480, miR-338-3p overexpression suppressed cell proliferation and migration and induced G1/S cell cycle arrest and apoptosis. By contrast, miR-338-3p knockdown significantly enhanced cell proliferation and migration, and suppressed G1/S cell cycle arrest and apoptosis. Furthermore, the dual-luciferase reporter assay confirmed MACC1 as a direct target of miR-338-3p. In addition, miR-338-3p overexpression reduced the level of MACC1 protein expression and MACC1 expression was significantly upregulated in CRC tissue samples. MACC1 siRNA significantly reduced CRC cell proliferation and migration, whilst cell apoptosis was significantly increased. In conclusion, miR-338-3p expression was decreased in CRC. miR-338-3p regulated the proliferation, apoptosis and migration of CRC cells by targeting MACC1.

Increased expression of DLX2 correlates with advanced stage of gastric adenocarcinoma.

AIM: To investigate the expression of distal-less homeobox 2 (DLX2) in gastric adenocarcinoma and its clinicopathological significance. METHODS: Gastric adenocarcinoma tissues were obtained from gastrectomy specimens of 129 patients from the Department of Surgery and Pathology, the Second Affiliated Hospital of Kunming Medical University. Sixty cases of normal gastric tissues were collected from gastrectomy specimens of adjacent gastric cancer margins greater than 5 cm. Patient diagnosis was established pathologically, and no patient had received chemotherapy or radiotherapy before surgery. All tissue specimens were formalin-fixed and paraffin-embedded. Immunohistochemistry was carried out to investigate the expression of DLX2 in 129 gastric adenocarcinoma tissues and 60 adjacent normal tissues. The immunostaining reaction was semiquantitatively evaluated based on the proportion of positive cells and the median staining intensity in normal gastric epithelial cells or tumor cells. All patients had follow-up records for more than 5 years. Correlations of DLX2 expression with clinicopathological features and prognosis of patients with gastric adenocarcinoma were analyzed. All statistical analyses were performed using the SPSS 17.0 software. RESULTS: The positive expression of DLX2 was detected in 68 (52.7%) cases of 129 gastric adenocarcinoma tissues and 14 (23.3%) cases of 60 adjacent normal tissues. The difference in DLX2 expression between gastric adenocarcinoma tissues and adjacent normal tissues was statistically significant (χ² = 14.391, P < 0.001). Moreover, high expression of DLX2 was detected in 48 (37.2%) cases of 129 human gastric cancer tissues, but not in adjacent normal tissues. The expression of DLX2 correlated with the size of tumor (P = 0.001), depth of invasion (P = 0.008), lymph node metastasis (P = 0.023) and tumor-node-metastasis stages (P = 0.020), but was not correlated with age, gender, histological differentiation and distant metastasis. The Kaplan-Meier survival analysis revealed that survival time of patients with high DLX2 expression was significantly shorter than that with low DLX2 expression. However, the multivariate analysis showed that invasion depth (P < 0.001), lymph nodes metastasis (P = 0.001) and distant metastasis (P < 0.001) were independent prognostic factors for patients with gastric adenocarcinoma, but DLX2 expression, tumor location and tumor size were not. CONCLUSION: These results suggest that increased expression of DLX2 may correlate with the advanced stage of gastric adenocarcinoma, and it may contribute to tumor development.

Ectopic expression of RASSF2 and its prognostic role for gastric adenocarcinoma patients.

RASSF2 has recently been identified as a potential tumor suppressor that serves as a Ras effector in various types of human cancers. However, there have been few reports detailing this in gastric cancer. Samples of gastric adenocarcinoma from 276 Chinese patients with follow-up were analyzed for RASSF2 protein expression by immunohistochemistry. RASSF2 was expressed in up to 31.2% (86/276) of this group of gastric carcinoma. The expression of RASSF2 was significantly lower in carcinomas than in normal mucosas (P<0.05). RASSF2 corresponded positively with patient age, histological differentiation, depth of tumor invasion, regional lymph node and distant metastasis, and TNM stage (all P<0.05). Further multivariate analysis revealed that patient gender, depth of tumor invasion, distant metastasis, TNM stage and the expression of RASSF2 were independent prognostic factors for patients with gastric cancer. The Kaplan-Meier plot showed that the overall mean survival time of the patients with RASSF2-negative expression was shorter than that of patients with positive expression (χ(2)=156.874, P<0.0001). Moreover, RASSF2-negative expression had a much more significant effect on the survival of those patients with early stage tumors (χ(2)=127.167, P<0.0001), highlighted by a >50.9% reduction in 3-year survival compared to that of patients with RASSF2-positive expression. In late stages, the difference was also significant (χ(2)=6.246, P=0.019), with a 35.5% reduction in 3-year survival. It is suggested that RASSF2 plays an important role in the evolution of gastric adenocarcinoma and should be considered as a potential marker for its prognosis.

Reduced Popdc3 expression correlates with high risk and poor survival in patients with gastric cancer.

AIM: To investigate the expression of Popeye domain containing 3 (Popdc3) and its correlation with clinicopathological features and prognosis of gastric cancer. METHODS: The method of immunohistochemistry was used to investigate the expression of Popdc3 in 306 cases of human gastric cancer and 84 noncancerous gastric tissues. Simultaneously, the relationship between Popdc3 expression and the survival of the patients was retrospectively analyzed. RESULTS: Popdc3 was detected in 72 (85.71%) of 84 human nontumor mucosa. High expression of Popdc3 protein was detected in 78 (25.49%) of 306 human gastric cancer cases, and low expression was detected in 228 (74.51%). Low expression of Popdc3 correlated with depth of invasion (P < 0.0001), regional lymph nodes (P < 0.0001) and distant metastasis (P = 0.02), and tumor, nodes, metastasis (TNM) stages (P < 0.0001). On multivariate analysis, only the patient's gender, regional lymph node metastasis, distant metastasis, TNM stages, and the expression of Popdc3 were independent prognostic factors in patients with gastric cancer. The Kaplan-Meier plot showed that low Popdc3 expression had a much more significant effect on the survival of those patients with early-stage tumors (χ² = 104.741, P < 0.0001), with a > 51.9% reduction in the three-year survival compared with high Popdc3 expression. In late stages, the difference was also significant (χ² = 5.930, P = 0.015), with a 32.6% reduction in the three-year survival. CONCLUSION: Reduced expression of Popdc3 may play a significant role in the carcinogenesis and progression of gastric cancer. Popdc3 may be an independent prognostic factor.

Abnormal expression of adhesion protein Bves is associated with gastric cancer progression and poor survival.

Although many molecular and biological studies have shown risk factors for gastric cancer, the available knowledge is still insufficient to unveil the exact mechanism of gastric cancer. To investigate the relationships between Bves expression and the clinicopathologic features of gastric cancer and whether Bves can act as prognostic indicators in gastric cancer. Tissues were obtained from the gastrectomy specimens of 306 human gastric cancer and 78 noncancerous gastric tissue at the Department of Surgery and Pathology, the Second Affiliated Hospital of Kunming Medical University from February 1996 to March 2007. The method of immunohistochemistry was used to investigate the expression of Bves in them. The relationship between Bves expression and the survival times of the patients was retrospectively analysed. Reduced expression of Bves frequently occurred in gastric cancer tissue. Low expression of Bves correlated with histologic differentiation, depth of invasion, regional lymph nodes and distant metastasis, and TNM stages (P < 0.05). Bves expression did not correlate with age, gender, location of tumor, size of tumor and histologic type (P > 0.05); Further multivariate analysis revealed that lymph node metastasis (P < 0.0001), distant metastasis (P < 0.0001), surgical treatment (P < 0.0001), and the expression of Bves (P < 0.0001) were independent prognostic factors in patients with gastric cancer; The Kaplan-Meier plot showed that survival times of patients with low Bves expression was significantly lower than those in patients with high Bves expression. Besides, low Bves expression had a much more significant effect on the survival of those patients with early stage tumors (χ2 = 131.216,P < 0.0001), highlighted by a >51.3% reduction in 3-year survival compared with that of patients with high Bves expression. In late stages, the difference was also significant (χ2 = 5.818,P = 0.016), with a 34.8% reduction in 3-year survival. Reduced expression of Bves in gastric cancer is associated with tumor progression and the patient's poor survival. This study showed that the studied protein has further provided a basis for the development of potential biomarker for gastric cancer prognosis.