Non-Coding RNA m6A Modification in Cancer: Mechanisms and Therapeutic Targets.

Recently, N6-methyl-adenosine (m6A) ribonucleic acid (RNA) modification, a critical and common internal RNA modification in higher eukaryotes, has generated considerable research interests. Extensive studies have revealed that non-coding RNA m6A modifications (e.g. microRNAs, long non-coding RNAs, and circular RNAs) are associated with tumorigenesis, metastasis, and other tumour characteristics; in addition, they are crucial molecular regulators of cancer progression. In this review, we discuss the relationship between non-coding RNA m6A modification and cancer progression from the perspective of various cancers. In particular, we focus on important mechanisms in tumour progression such as proliferation, apoptosis, invasion and metastasis, tumour angiogenesis. In addition, we introduce clinical applications to illustrate more vividly that non-coding RNA m6A modification has broad research prospects. With this review, we aim to summarize the latest insights and ideas into non-coding RNA m6A modification in cancer progression and targeted therapy, facilitating further research.

Synergistic antitumor effect of a γ-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma.

As a multi-kinase inhibitor, sorafenib is beneficial in around 30% of hepatocellular carcinoma (HCC) patients; however, HCC patients develop acquired drug resistance quickly. Clinical benefits of sorafenib, in combination with transarterial chemoembolization (TACE), radiotherapy, and other chemodrugs are limited. We investigated the efficacy and mechanisms of Notch signaling inhibition as adjuvant to sorafenib in HCC spheroid-derived in vitro and in vivo tumor models, using the γ-secretase inhibitor (GSI), PF-03084014. The combination of PF-03084014 plus sorafenib inhibited proliferation and self-renewal of HCC spheroids (stem-like cancer cells). PF-03084014 significantly enhanced antitumor activity of sorafenib; both agents at low dose reached synergistic tumor growth suppression of HCC spheroid-derived orthotopic tumors. The Notch1-Snail1 signaling pathway contributed to sorafenib resistance via increasing epithelial-mesenchymal transition (EMT) and EMT-mediated cancer stem cell (CSC) features, such as increased expression of Snail1, N-cadherin, ABCG2, and the stem cell related genes Nanog and Oct4, and decreased expression of E-cadherin. Anti-tumor activity of the combination therapy was associated with decreased expression of survival signals (Mek/Erk, PI3K/Akt) and reduced microvessel density. PF-03084014 plus sorafenib targets Notch1-Snail1 signaling to reverse EMT and EMT-mediated CSC stemness in the tumors. These synergistic effects provide a rationale to utilize GSIs, in combination with sorafenib, as a new therapeutic strategy for the treatment of HCC.

Blocking CDK1/PDK1/ß-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma.

Rationale: Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/ß-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential. Methods: CDK1 overexpression and clinicopathological parameters were analyzed. HCC patient-derived xenograft (PDX) tumor models were treated with RO3306 (4 mg/kg) or sorafenib (30 mg/kg), alone or in combination. The relevant signaling of CDK1/PDK1/ß-Catenin was measured by western blot. Silencing of CDK1 with shRNA and corresponding inhibitors was performed for mechanism and functional studies. Results: We found that CDK1 was frequently augmented in up to 46% (18/39) of HCC tissues, which was significantly associated with poor overall survival (p=0.008). CDK1 inhibitor RO3306 in combination with sorafenib treatment significantly decreased tumor growth in PDX tumor models. Furthermore, the combinatorial treatment could overcome sorafenib resistance in the HCC case #10 PDX model. Western blot results demonstrated the combined administration resulted in synergistic down-regulation of CDK1, PDK1 and ß-Catenin as well as concurrent decreases of pluripotency proteins Oct4, Sox2 and Nanog. Decreased CDK1/PDK1/ß-Catenin was associated with suppression of epithelial mesenchymal transition (EMT). In addition, a low dose of RO3306 and sorafenib combination could inhibit 97H CSC growth via decreasing the S phase and promoting cells to enter into a Sub-G1 phase. Mechanistic and functional studies silencing CDK1 with shRNA and RO3306 combined with sorafenib abolished oncogenic function via downregulating CDK1, with downstream PDK1 and ß-Catenin inactivation. Conclusion: Anti-CDK1 treatment can boost sorafenib antitumor responses in PDX tumor models, providing a rational combined treatment to increase sorafenib efficacy in the clinic.

Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3.

Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma, indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (γ-secretase inhibitor) PF-03084014 in hepatocellular carcinoma. Hepatocellular carcinoma spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the hepatocellular carcinoma sphere-derived orthotopic tumor and blocked the hepatocellular carcinoma tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced hepatocellular carcinoma sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial-mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch-Stat3 association was implicated in the clinical hepatocellular carcinoma prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of gamma-secretase inhibitors as a therapeutic option for the treatment of hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1531-43. ©2017 AACR.

Enucleation is Better for a Giant Hemangioma Proximal to the Hepatic Portal Vascular Structures.

The aim of this study is to compare the effect of liver enucleation with resection of a giant hemangioma proximal to the hepatic portal vascular structures. From 2008 to 2014, 53 patients with giant hemangiomas proximal to the hepatic portal vascular structures underwent surgery in our hospital by the same surgical team. The indications for surgery included a tumor size greater than 8 cm, a middle size greater than 4 cm but with abdominal pain, a rapidly increased tumor size with uncertain malignancy, or tumor rupture. Thirty-two patients (60 %) had pain only, 15 (29 %) had pain with tumor growth, 5 patients (9 %) had an uncertain diagnosis, and 1 patient (2 %) had tumor rupture. Enucleation was performed in 31 patients and liver resection was performed in 22 patients. There were no significant differences in the size of the hemangioma (13.9 ± 3.1 vs 12.3 ± 5.5 cm; P > 0.05), preoperative liver function tests, hemoglobin levels, and platelet counts between the enucleation and resection groups. The mean intraoperative blood loss was significantly less in the enucleation group compared with the resection group (350.9 ± 89.8 vs 988 ± 91.7 mL; P < 0.01), and the enucleation group had a significantly shorter mean operative time (1.7 ± 0.4 vs 2.9 ± 0.9 h; P < 0.01) and significantly shorter duration of hospital stay (9.6 ± 4.2 vs 14.7 ± 3.7 days; P < 0.05). Five patients in the resection group and only 1 patient in the enucleation group had major postoperative complications. Compared to liver resection, enucleation is safer and faster for liver hemangiomas proximal to the hepatic portal vascular structures and is associated with fewer complications.

Rare case of omentum-wrapped abscess caused by a fish bone penetrating the terminal ileum.

Accidentally ingested foreign bodies, for the most part, pass through the gastrointestinal tract, but can cause several complications. Perforation is rare, but can occur in any segment of the gastrointestinal tract. Intestinal perforations due to foreign bodies are rarely diagnosed preoperatively as clinical symptoms are non-specific and they can mimic other abdominal conditions. We describe a case of a 48-year-old patient who was admitted to the emergency room because of severe abdominal pain of 5 d duration. A computed tomography scan showed an undefined liquid collection involving a linear image 35 mm in size, suggestive of a foreign body. On laparotomy, an abscess containing a fish bone was resected. As fish bone ingestion is usually not remembered by the patient, the diagnosis can be delayed. The preoperative diagnosis is frequently acute abdomen of unknown cause. A low threshold of suspicion along with a good clinical history and radiological studies are extremely important in order to make a correct diagnosis.

Spontaneous rupture of primary splenic angiosarcoma: a case report and literature review.

BACKGROUND: Primary angiosarcoma of the spleen is a rare mesenchymal malignant tumor of vascular origin often with a poor prognosis, due to its high metastatic potential. This disease often presents with atraumatic rupture and lethal hemorrhage. CASE PRESENTATION: We report a case of a 65-year-old man who presented with abdominal pain, anemia, thrombocytopenia, and palpable abdominal mass with unstable blood pressure. Laparotomy revealed a huge actively bleeding spleen, thus splenectomy was performed. Some liver metastasis foci were also found during the procedure. Histopathology diagnosis of the removed spleen was primary splenic angiosarcoma. The patient was discharged on the 10th day post operation with no complication. CONCLUSIONS: Splenic angiosarcoma should be considered one of the differential diagnoses in patients with spleen parenchymal lesions. Definitive diagnosis requires laparotomy followed by splenectomy. In the majority of the patients with spleen angiosarcoma, metastatic diseases have already occurred at the time of laparotomy, so splenectomy is an approach more for diagnostic purpose rather than curative purpose.