Mig6 not only inhibits EGFR and HER2 but also targets HER3 and HER4 in a differential specificity: Implications for targeted esophageal cancer therapy.

The human EGF receptor family plays pivotal roles in physiology and cancer, which contains four closely-related members: HER1/EGFR, HER2, HER3 and HER4. Previously, it was found that the mitogen-inducible gene 6 (Mig6) protein is a negative regulator of EGFR and HER2 by using its S1 segment to bind at the kinase dimerization interface. However, it is still unclear whether the S1 segment can also effectively target HER3 and HER4? Here, we performed a systematic investigation to address this issue. The segment can bind to all the four HER kinases with a varying affinity and moderate selectivity; breaking of the segment into shorter hotspot peptides would largely impair the affinity and selectivity, indicating that the full-length sequence is required for the effective binding of S1 to these kinases. The hs2 peptide, which corresponds to the middle hotspot region of S1 segment, can partially retain the affinity to HER kinases, can moderately compete with S1 segment at the dimerization interfaces, and can mimic the biological function of Mig6 protein to suppress HER4+ esophageal cancer at cellular level. In addition, we also analyzed the binding potency of S1 segment and hs2 peptide to the kinase domains of other five widely documented growth factor receptors (GFRs). It was showed that both the S1 and hs2 cannot effectively interact with these receptors. Overall, the Mig6 is suggested as a specific pan-HER inhibitor, which can target and suppress HER family members with a broad selectivity, but exhibits weak or no activity towards other GFRs.

Correlation Between Single Nucleotide Polymorphisms of an miRNA Binding Site in the 3'UTR of PTEN and Risk of Cervical Cancer Among the Han Chinese.

Objective: To analyze the association between a single nucleotide polymorphism (SNP) in the 3' untranslated region (UTR) of the phosphatase and tensin homolog (PTEN) gene, that is within a microRNA (miRNA) binding site, and the risk of Chinese Han cervical cancer. Methods: A case-control study was carried out to analyze the genotype of the PTEN rs34140758 locus in 210 surgically treated, Han Chinese, cervical cancer patients and 210 healthy controls. The levels of the miRNAs hsa-miR-586 and hsa-miR-622 and the PTEN mRNA were analyzed by real-time reverse transcription-quantitative polymerase chain reaction in the cancerous and adjacent normal tissues from all cases. HeLa cells were transfected with the miRNAs, hsa-miR-586 and hsa-miR-622, to analyze their effects on PTEN gene expression. Results: After adjusting for age, body-mass index, alcohol consumption, smoking, and familial history of cancer, the PTEN rs34140758 A allele carriers were 1.47 times more likely to suffer from cervical cancer than the C allele carriers (odds ratio [OR] = 1.47, 95% confidence interval [CI]: 1.17-1.72, p = 0.001). Both hsa-miR-586 and hsa-miR-622 were highly expressed in the cancerous tissues of the cervical cancer patients, whereas PTEN expression was low. HeLa cell transfection experiments showed that hsa-miR-586 and hsa-miR-622 inhibited PTEN gene expression. The results of a dual-luciferase reporter assay showed that the PTEN gene is a target for both hsa-miR-586 and hsa-miR-622. Conclusion: The PTEN 3'UTR rs34140758 locus SNP is associated with the risk of cervical cancer in the Han Chinese population. The molecular mechanism may be that the rs34140758 SNP affects the regulation of PTEN gene expression through interaction with the hsa-miR-586 and hsa-miR-622 miRNAs.

APC gene 3'UTR SNPs and interactions with environmental factors are correlated with risk of colorectal cancer in Chinese Han population.

OBJECTIVE: To study the correlation between adenomatous polyposis coli (APC) gene 3' untranslated region (UTR) single nucleotide polymorphisms (SNPs) and their interactions with environmental factors and the risk of colorectal cancer (CRC) in a Chinese Han population. METHODS: Genotypes of APC gene 3'UTR rs1804197, rs41116, rs448475, and rs397768 loci in 340 Chinese Han patients with CRC and 340 healthy controls were analyzed. All patients with CRC were analyzed for progression-free survival (PFS) during a 3-year follow-up. RESULTS: The risk of CRC in subjects carrying the APC gene rs1804197 A allele was 2.95-times higher than for the C allele carriers. The interactions of the rs1804197 SNP with body mass index (BMI) and smoking were associated with the risk of CRC. The risk of CRC in the APC gene rs397768 G allele carriers was 1.68-times higher than in the A allele carriers. The interaction between the rs397768 locus SNP and gender was also associated with the risk of CRC. The 3-year PFS of patients with APC gene rs1804197 AA genotype, CA genotype, and CC genotype CRC decreased in this order, with significant difference. In addition, the 3-year PFS of rs397768 locus GG genotype, AG genotype, and AA genotype CRC patients decreased in this order, and the difference was significant. CONCLUSION: The rs1804197 locus in the 3'UTR region of the APC gene and its interactions with BMI and smoking are associated with the risk of CRC in a Chinese Han population. In addition, the interaction between rs397768 locus SNP and gender is related to the risk of CRC.

The ATM rs189037 G>A polymorphism is associated with the risk and prognosis of gastric cancer in Chinese individuals: A case-control study.

The ataxia telangiectasia mutated (ATM) gene is involved in repairing DNA lesions and maintaining genome stability, which is related to cancer invasion and metastasis. This gene influences the risk of cancers. Many studies have demonstrated that the ATM rs189037 G>A polymorphism is linked with the risks of different types of cancer. However, no study has probed the relationship between the ATM rs189037 G>A polymorphism and gastric cancer (GC) risk. Therefore, the aims of this study were to investigate the association of the ATM rs189037 G>A polymorphism with the risk and prognosis of GC in a case-control investigation of 345 GC patients and 467 controls in China. The rs189037 G>A polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism. This polymorphism was related to a significantly higher risk of GC [AA vs. GG: OR (95% CI): 1.80 (1.20-2.70), P = 0.04; GG vs. AA + GA: 1.46 (1.08-1.98); A vs. G: 1.34 (1.10-1.64), P = 0.004]. Subgroup analyses showed significant associations with female gender, smoking, alcohol consumption, age ≥60 years, and positive Helicobacter pylori status. This polymorphism was also correlated with TNM stage III + IV and tumor size >4 cm. GC patients carrying the AA genotype of the rs189037 polymorphism also had lower overall survival. In conclusion, the ATM rs189037 G>A polymorphism was related to increased susceptibility to and poorer prognosis in GC in this Chinese population.