[Molecular study of an individual with Bel subtype due to a novel c.620T>C variant].

OBJECTIVE: To explore the molecular basis for an individual with Bel subtype of the ABO blood type due to a novel c.620T>C variant gene, and assess its impact on the structure of GTB transferase. METHODS: An individual who had visited the First Affiliated Hospital of Zhengzhou University on February 11, 2023 was selected as the study subject. ABO phenotyping was initially conducted with serological methods, which was followed by direct sequencing of 7 exons of the ABO gene. Subsequently, single-strand sequencing was carried out by using allele-specific primers, and the variant in the B transferase was homology-modeled using the Modeller software. The impact of the variant on the transferase's spatial structure was analyzed with the PyMOL software. RESULTS: The serological phenotype of the patient was identified as the Bel subtype. Direct sequencing revealed that she has harbored a novel c.620T>C variant, resulting in a p.Leu207Pro substitution in the polypeptide chain. Combined with single-strand sequencing, her genotype was ultimately determined as ABO*BELnew/ABO*O.01.02. Three-dimensional protein structure modeling showed that, compared with the wild type, the distance of one hydrogen bond between Proline and Glycine at position 272 has increased, along with disappearance of another hydrogen bond. CONCLUSION: The novel c.620T>C (p.Leu207Pro) variant of B allele may affect the structural stability of the glycosyltransferase. The weakened enzyme activity in turn may lead to reduced B antigen expression, manifesting as the Bel subtype by serological analysis.

LncHOXA10 drives liver TICs self-renewal and tumorigenesis via HOXA10 transcription activation.

BACKGROUND: Liver cancer is one of the most deadly cancers in the world. There are various cells in liver tumor bulk, including liver tumor initiating cells (TICs), which account for liver tumorigenesis, drug resistance, relapse and metastasis. The homeobox (HOX) transcription factors play critical roles in many physiological and pathological processes, while, their roles in liver TICs and liver tumorigenesis remain unknown. METHODS: An unbiased screening was performed using online-available datasets. Liver TICs were sorted by FACS using surface markers CD133, CD13 and EPCAM, or enriched by oncosphere formation assay. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, Western blot and double FISH were used to explore the molecular mechanism of lncRNA. RESULTS: Here, we examined the expression pattern of HOX transcription factors, and found HOXA10 was overexpressed in liver cancer samples. Moreover, a divergent lncRNA of HOXA10 (termed lncHOXA10 hereafter) was also highly expressed in liver cancer and liver TICs. LncHOXA10 drove liver TIC self-renewal and liver tumorigenesis through HOXA10-dependent manner. LncHOXA10 interacted with SNF2L and recruited NURF chromatin remodeling complex to HOXA10 promoter, and thus initiated the transcription of HOXA10. Through HOXA10 transcriptional regulation, lncHOXA10 activated HOXA10 in liver TICs. LncHOXA10-HOXA10 signaling can be targeted to eliminate liver TICs. Altogether, lncHOXA10 drove HOXA10 expression and thus promoted liver TIC self-renewal. CONCLUSION: HOXA10 was the most highly expressed HOX transcription factor in liver cancer and liver TICs. LncHOXA10 drove the transcriptional activation of HOXA10. This work revealed the important role of HOX transcription factor in liver TIC self-renewal and added a new layer for liver TIC regulation.

LncRNA TUG1 interacting with miR-144 contributes to proliferation, migration and tumorigenesis through activating the JAK2/STAT3 pathway in hepatocellular carcinoma.

Recently, it is reported that taurine upregulated gene 1 (TUG1) participates in the tumor progression by acting as a competing endogenous RNA (ceRNA) of miRNAs. Nonetheless, whether TUG1 could serve as a ceRNA of miR-144 in hepatocellular carcinoma (HCC) progression remains undefined. Here, our results indicated that there was a marked rise in TUG1 expression in HCC tissues and cells, and downregulation of TUG1 hindered proliferation and migration of HCC cells. Additionally, TUG1 was validated to act as a molecular sponge of miR-144. Furthermore, we found that TUG1 interacting with miR-144 contributed to proliferation and migration of HCC cells via activating the JAK2/STAT3 pathway in vitro. Moreover, TUG1 knockdown inhibited HCC tumor growth in vivo through upregulating miR-144 via inactivation of the JAK2/STAT3 pathway. In conclusion, TUG1 interacting with miR-144 contributed to proliferation, migration and tumorigenesis through activation of the JAK2/STAT3 pathway in HCC.

MicroRNA-30a Mediates Cell Migration and Invasion by Targeting Metadherin in Colorectal Cancer.

MicroRNAs play critical roles in the occurrence and progression in various cancers including colorectal cancer. Here, we found that microRNA-30a expression was significantly downregulated in colorectal cancer tissues compared to adjacent noncancerous tissues, and the suppression levels of microRNA-30a were significantly associated with tumor differentiation and lymph node metastasis. We also discovered that the expression level of microRNA-30a was inversely proportional to the invasive potential of several colorectal cancer cell lines. Moreover, overexpression of microRNA-30a in colorectal cancer cells inhibited activity of cell migration and invasion. Luciferase reporter assay confirmed metadherin could be a direct target of microRNA-30a, as the overexpression of microRNA-30a decreased metadherin expression at both the protein and messenger RNA levels. Furthermore, the knockdown of metadherin expression in SW620 significantly decreased cell metastasis and invasion. The upregulation of metadherin at the protein level negatively correlated with the expression of microRNA-30a in colorectal cancer tissues, and this upregulation could partially attenuate the effect induced by microRNA-30a. These findings indicate that microRNA-30a may act as a tumor suppressor in colorectal cancer and that microRNA-30a represses cell migration and invasion by decreasing metadherin, highlighting the therapeutic potential of microRNA-30a and metadherin in colorectal cancer treatment.

[Comparison of Weak ABO Antigen and Normal ABO Antigen in Patients with Acute Leukemia].

OBJECTIVE: To compare the differences between weak ABO antigen patients and normal ABO antigen patients with acute leukemia, and to explore the clinical significance of weak ABO antigen in acute leukemia. METHODS: The ABO blood group was detected in 110 newly diagnosed acute leukemia patients(including 68 cases of AML and 42 cases of ALL) and 68 normal controls. Then the leukemia subtype, age, sex, laboratory test, risk status of leukemia patients, and DNA methylation of ABO promoter were compared between patients with weak and normal ABO antigen. RESULTS: The weak ABO antigen was found in patients with newly diagnosed acute leukemia, and was not found in ALL patients or normal group. No statistical differences were found in the distribution of ABO blood group, age, hepatosplenomegaly, lymphadenovarix, plt, precursor cell clusters derived from bone marrow, immunopheno-typing, LDH level, and risk status between AL patients of weak and normal ABO antigen groups (P>0.05). Compared with patients in normal ABO antigen group, the pateins in weak ABO antigen group had higher percentage of male(77.8% vs 30%), lower WBC(32.26×109/L vs 82.69×109/L) and Hb level(64.00 g/L vs 85.94 g/L) and higher DNA methylation level (18.91% vs 10.76%) (P<0.05). CONCLUSION: The cases of weak ABO antigen frequently appear in the male AML patients, the DNA methylation level of ABO gene promoter in patients with weak ABO antigen is significantly higher than that in patients with normal ABO antigen.