Chunhong Hu

Annexin A5 inhibits diffuse large B-cell lymphoma cell invasion and chemoresistance through phosphatidylinositol 3-kinase signaling.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkins lymphoma worldwide. Although patient outcomes have significantly improved to a greater than 40% cure rate by the combinatorial cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, which is widely used, resistance to the CHOP regimen continues to pose a problem in managing or curing DLBCL. While it promotes the malignancy and chemo-resistance in certain types of cancer, Annexin A5 is negatively correlated with those in other cancers, including DLBCL. In the present study, we explored the effects of Annexin A5 on DLBCL cell invasion and chemoresistance to CHOP. Stable overexpression and knockdown of Annexin A5 were performed in Toledo and Pfeiffer human DLBCL cell lines. Overexpression of Annexin A5 in both cell lines significantly decreased cell invasion, matrix metalloproteinase-9 (MMP-9) expression/activity, phosphatidylinositol 3-kinase (PI3K) activity/Akt phosphorylation, and cell survival against CHOP-induced apoptosis. On the other hand, knockdown of Annexin A5 markedly increased cell invasion, MMP-9 expression/activity, PI3K activity/Akt phosphorylation, and CHOP-induced apoptosis in the DLBCL cell lines, which was abolished by selective PI3K inhibitor BKM120. In conclusion, our study provides the first in vitro evidence that Annexin A5 inhibits DLBCL cell invasion, MMP-9 expression/activity, and chemoresistance to CHOP through a PI3K-dependent mechanism; it provides new insight not only into the biological function of Annexin A5, but also into the molecular mechanisms underlying DLBCL progression and chemoresistance.

XRCC1 genetic polymorphism acts a potential biomarker for lung cancer.

Lung cancer is one of the most common but serious cancers in the world. Both the X-ray repair cross-complementing group 1 (XRCC1) gene and the human multidrug resistance 1 (MDR1) gene are important candidate genes influencing the susceptibility to various diseases, including lung cancer. This study aimed to assess the correlation of genetic polymorphisms in XRCC1 and MDR1 with the susceptibility to lung cancer. In this study, a total of 320 lung cancer patients and 346 cancer-free controls in Chinese population were enrolled in this study. Data about the clinical characteristics and related risk factors of lung cancer were collected by questionnaires. The single-nucleotide polymorphisms (SNPs) of XRCC1 and MDR1 genes were genotyped by created restriction site-polymerase chain reaction method. Our data showed that the risk for lung cancer increased significantly among the variant Arg194Trp (C > T, rs1799782) and Arg399Gln (G > A, rs25487) of XRCC1, but there are no significant differences in the allelic and genotypic frequencies of c.1564A > T and c.3073A > C of MDR1 between lung cancer patients and cancer-free controls. In conclusion, these preliminary results suggest that the C > T, rs1799782 and C > T, rs25487 of XRCC1 genetic variants might be used as molecular markers for detecting lung cancer susceptibility.

Rab25 GTPase: Functional roles in cancer

Rab25, a small GTPase belongs to the Rab protein family, has a pivotal role in cancer pathophysiology. Rab25 governs cell-surface receptors recycling and cellular signaling pathways activation, allowing it to control a diverse range of cellular functions, including cell proliferation, cell motility and cell death. Aberrant expression of Rab25 was linked to cancer development. Majority of research findings revealed that Rab25 is an oncogene. Elevated expression of Rab25 was correlated with poor prognosis and aggressiveness of renal, lung, breast, ovarian and other cancers. However, tumor suppressor function of Rab25 was reported in several cancers, such as colorectal cancer, indicating the tumor type-specific function of Rab25. In this review, we recapitulate the current knowledge of Rab25 in cancer development and therapy.

MicroRNA-19a promotes nasopharyngeal carcinoma by targeting transforming growth factor β receptor 2

MicroRNA (miR), a class of small non-coding RNA, function as key regulators in gene expression through directly binding to the 3′ untranslated region of their target mRNA, which further leads to translational repression or mRNA degradation. miR-19a, a member of miR-17-92 cluster, has an oncogenic role in a variety of malignant tumors. However, the exact role of miR-19a in nasopharyngeal carcinoma (NPC) has not previously been studied. The present study aimed to investigate the function and mechanism of miR-19a in regulating the viability and invasion of NPC cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) data indicated that the expression levels of miR-17-92 cluster members (miR-17, miR-18a, miR-19a and miR-20a) were frequently increased in NPC tissues compared to the normal tissues. It was also demonstrated that miR-19a was significantly upregulated in NPC C666-1 cells compared to NP69 cells (P<0.01). Knockdown of miR-19a led to a significant decrease in the viability and invasion of NPC C666-1 cells (P<0.01), and induced increased protein expression levels of transforming growth factor β receptor 2 (TGFβR2), which was further identified as a direct target gene of miR-19a by using a luciferase reporter assay. Overexpression of TGFβR2 also suppressed the viability and invasion of C666-1 cells, similar to the effects of miR-19a inhibition. Furthermore, knockdown of TGFβR2 reversed the suppressive effects of miR-19a inhibition on C666-1 cell viability and invasion, suggesting that the role of miR-19a in mediating cell viability and invasion is through directly targeting TGFβR2 in NPC cells. In addition, RT-qPCR data demonstrated that the mRNA expression level of TGFβR2 was markedly reduced in NPC tissues and C666-1 cells. In summary, the present study demonstrated an oncogenic role of miR-19a in NPC via mediation of TGFβR2. Therefore, miR-19a may be a potential therapeutic target for NPC.

Molecular characterization and therapeutic reaction to dasatinib in a CML patient harboring a novel e8a2 BCR-ABL1 transcript with a somatic mutation in TP53BP2 and cadherin-10 genes

Chronic myeloid leukemia (CML) results from the neoplastic transformation of hematopoietic stem cells harboring the t(9;22)(q34;q11) translocation that is the genetic hallmark of CML. This rearrangement generates the hybrid BCR-ABL1 gene consisting of the typical e13a2 or e14a2 transcripts. In addition, the junction between BCR and ABL1 in fewer than 5% of cases is unusual, including e1a2, e19a2, e6a2, e8a2, e13a2, and e18a2, with a breakpoint outside the major BCR region or with a deletion/ insertion within e13a2 or e8a2 involving a third splicing locus [1–5]. Although e8a2 transcripts have been reported previously [3–5], a change of down-stream signaling driven by variant BCR-ABL1 has not yet been revealed. Here we present a CML patient carrying a novel e8a2 BCR-ABL1 transcript with a 2-bp deletion that coexisted with a somatic mutation of TP53BP2 and cadherin-10 (CDH10) gene. Clinically, the patient had a good response to dasatinib treatment in terms of molecular remission and somatic mutations in TP53BP2 and CDH10 genes were no longer detected. A 49-year-old man was referred to our department for the evaluation of leukocytosis in January of 2016. He complained of fatigue, facial and palpebral conjunctiva congestion. Prior to this evaluation, the patient had taken a routine medical examination in Jun 2015 and was found to have abnormal hematological parameters: white blood cell (WBC) at 22.41 10/L (74.3% neutrophils, 17% lymphocytes, 4.7% eosinophils, and 4.0% basophils), hemoglobin of 154g/L, and a platelet count of 420 10/L. A visit to another hospital in Changsha city showed that his spleen was not palpable. The bone marrow aspirate indicated a hypercellular marrow with significantly megakaryocytic hyperplasia. BCR-ABL1 transcript amplifications covering e13a2 or e14a2 were negative and somatic mutation of Janus Kinase 2 gene (JAK2V617F) was absent. He was diagnosed with myeloproliferative neoplasm (MPN, unclassifiable) and given low-dose hydroxyurea combined with interferon-a therapy. Although the patient achieved complete hematological response after 4.5 months, he terminated the treatment due to intolerance to interferon-a. At presentation, his spleen was not palpable. Blood cell counts were as follows: WBC of 30.77 10/L with a differential count of 75.0% neutrophils, 14% lymphocyte, 1% monocytes, 1% eosinophils, and 9% Basophils; hemoglobin of 154 g/L and platelet count of 449 10/L. The bone marrow aspirate showed hypercellular marrow with left-shifted mature myeloid neutrophils and megakaryocytic hyperplasia. The BCRABL1 transcripts, e13a2/e14a2 (P210), e1a2 (P190), and e19a2 (P230) were under the lower-limit of detection. The mutations of JAK2-V617F, exon 12 of JAK2, exon 9 of CALR, or exon 10 of MPL gene were absent. Chronic neutrophilic leukemia (CNL) or atypical chronic leukemia (aCML) associated mutations in CSF3R and SETBP1 were negative. Fluorescence in situ hybridization (FISH) assay using specific dual-color BCR-ABL1 ES probes revealed the presence of t(9;22) translocation (Figure 1(A)). To quantify variant BCR-ABL1 transcript (e8a2), real-time quantitative PCR (RQ-PCR) was carried out with specific forward primers: 50-CCTGAGAGCCAGA AGCAACAAAGATG CC-30 (BCR exon 8) and reverse primers: 50-CCATTGTGATTATAGCCT AAGACCCGGAG-30 (ABL1 exon 2). BCR-ABL1 quantification was performed using the purified PCR products to establish a standard curve. The result was expressed as the BCR-ABL1:ABL1 ratio with no conversion of the international scale (IS). RT-PCR amplified a single PCR fragment (442 bp) (Figure 1(B)). Compared to the reported e8a2 transcript, Sanger sequencing identified the presence of a novel e8a2 rearrangement carrying a deletion that was localized at the last 2-bp (AG) nucleotide of the 30 end of BCR exon 8 (Figure 1(C)). BLAST analysis suggested that the open reading frame was preserved and the structure of the active tyrosine kinase domain of ABL1 was not changed except for a deletion of the

Tumor-derived exosomes in cancer metastasis risk diagnosis and metastasis therapy

Exosomes are endosomes secreted from the membrane by exocytosis as multivesicular bodies and are generally defined by their spherical, unilamellar morphology, size and the expression of specific biomarkers used for diagnosis or therapy targets. Recent research has reported a higher relationship between exosome enrichment and tumor disease development. In this review, we discuss exosome intercellular communication and functions in the pathology of disease, especially on the cancer metastasis related with exosome. We introduce how exosomes from cancer and stem cancer cells target different organs through transporting molecular proteins of exosome inclusions to improve or inhibit cancer metastasis as well as highlight exosome therapy strategies for tumor pathology involving microRNAs.

Intensity modulated radiation therapy to treat primary female mediastinal seminoma and massive pericardial effusion: A case report

Primary mediastinal seminoma is a rare extragonadal germ cell tumour that mainly occurs in males. The present study reports the case of a 27-year-old woman that presented with superior vena cava syndrome and a large mass in the mediastinum, which was diagnosed as primary female mediastinal seminoma. The patient received 6 cycles of cisplatin-based chemotherapy [4 cycles BEP chemotherapy (120 mg cisplatin, 0.45 g etoposide and 60 mg bleomycin, once every 3 weeks); 2 cycles IEP chemotherapy (120 mg cisplatin, 100 mg epirubicin and 6 g ifosfamide, once every 3 weeks)] and the patient showed an increase in the size of the mediastinal mass and hydropericardium, indicating a resistance to chemotherapy. Radiotherapy to the mediastinum (50 Gy over 18 fractions) and pericardium (30 Gy over 18 fractions) was performed. Following radiotherapy, the patient was considered to have a complete response to the treatment, and subsequent to a 5-year follow-up, no recurrence or metastasis was identified. To the best of our knowledge, no similar cases have been reported in the literature at present.

Association between Wnt inhibitory factor 1 and receptor tyrosine kinase-like orphan receptor 2 protein expression and the clinical pathological significance in benign and malignant pancreatic lesions

Pancreatic cancer is one of the most malignant types of tumor. It is important to elucidate the underlying molecular mechanisms of pancreatic tumorigenesis and to identify novel biomarkers as therapeutic targets of pancreatic cancer. In the present study, the protein expression levels of Wnt inhibitory factor 1 (WIF1) and receptor tyrosine kinase-like orphan receptor 2 (ROR2) were examined in a collection of pancreatic ductal carcinoma and benign pancreatic lesion tissue samples using immunohistochemistry. The positive expression rate of WIF1 protein in pancreatic ductal carcinoma was demonstrated to be significantly decreased compared with that of the paracancerous tissue, benign lesions and wild-type pancreatic tissue (P=0.002, P<0.0001, P=0.001, respectively). The positive expression rate of ROR2 protein in pancreatic ductal carcinoma was demonstrated to be significantly increased compared with that of the paracancerous tissue, benign lesions and wild-type pancreatic tissue (P<0.0001). There was a negative association between WIF1 and ROR2 expression in the pancreatic ductal carcinoma samples (P=0.004). The survival period of patients with negative WIF1 and positive ROR2 protein expression was demonstrated to be significantly decreased compared with that of patients with positive WIF1 and negative ROR2 protein expression (P<0.0001). The expression levels of WIF1 and ROR2 protein reflected the incidence, development, clinical and biological behavior, and prognosis of pancreatic ductal carcinoma. Patients with negative WIF1 and positive ROR2 protein expression had poor prognosis. The results indicate that WIF1 and ROR2 are important biomarkers in pancreatic cancer.

Synchronous colorectal cancer and multiple myeloma with chest wall involvement: Is this a coincidence?

Multiple primary malignant neoplasms (MPMNs) are rare malignant neoplasms that simultaneously or successively occur in the same patient as 2 or more primary malignancies. Currently, an increasing number of cases are being reported. In general, MPMNs more commonly occur as 2 solid tumors or 2 hematological malignancies. Cases of MPMN that involve a solid tumor and a hematological malignancy are rare. Here, we report a case of synchronous colorectal cancer (CRC) and multiple myeloma (MM) with chest wall involvement. After reviewing the literature, we believe that there may be a distinct syndrome involving CRC and MM. The patient in our case study suffered refractory anemia following surgery and 2 cycles of chemotherapy. Initially, the anemia was considered to be a common manifestation of CRC in this patient. Interestingly, although he received a blood transfusion, his hemoglobin levels remained low. He later developed hematuria, proteinuria, multiple osteoporosis in the costal bones, and thrombocytopenia. These new symptoms drew our attention, and we considered a diagnosis of synchronous primary CRC and MM, with the anemia as a symptom of MM. Based on the results of a bone marrow aspirate, MM was confirmed. Therefore, when CRC is associated with refractory anemia, we should not only assume that anemia is a classical symptom of CRC, a result of chronic blood loss, nutritional deficiencies, or myelosuppression due to chemotherapy, but we should also consider that it may reflect the possibility of a coexisting hematologic malignancy. As the treatment of these 2 malignancies is different, early diagnosis and treatment based on definitive diagnosis as early as possible will be beneficial to overall prognosis.