Inhibition of RhoGEF/RhoA alleviates regorafenib resistance and cancer stemness via Hippo signaling pathway in hepatocellular carcinoma.

Patients with hepatocellular carcinoma (HCC) are vulnerable to drug resistance. Although drug resistance has been taken much attention to HCC therapy, little is known of regorafenib and regorafenib resistance (RR). This study aimed to determine the drug resistance pattern and the role of RhoA in RR. Two regorafenib-resistant cell lines were constructed based on Huh7 and Hep3B cell lines. In vitro and in vivo assays were conducted to study RhoA expression, the activity of Hippo signaling pathway and cancer stem cell (CSC) traits. The data showed that RhoA was highly expressed, Hippo signaling was hypoactivated and CSC traits were more prominent in RR cells. Inhibiting RhoA could reverse RR, and the alliance of RhoA inhibition and regorafenib synergistically attenuated CSC phenotype. Furthermore, inhibiting LARG/RhoA increased Kibra/NF2 complex formation, prevented YAP from shuttling into the nucleus and repressed CD44 mRNA expression. Clinically, the high expression of RhoA correlated with poor prognosis. LARG, RhoA, YAP1 and CD44 show positive correlation with each other. Thus, inhibition of RhoGEF/RhoA has the potential to reverse RR and repress CSC phenotype in HCC.

Toxicity study of compound granules of Hedyotis diffusa: Acute toxicity and long-term toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: The clinical efficacy of the hospital preparation compound granules of Hedyotis diffusa (CGHD), which is composed of Hedyotis diffusa Willd, Smilax china L., Solanum lyratum Thunb., has accumulated a good reputation over the past decades. However, because it is a hospital preparation, few researchers have paid attention to it, resulting in a lack of systematic basic research studies. Thus, it is not clear whether there are safety concerns that restrict its clinical application, and toxicological evaluation of CGHD is needed. AIM OF THE STUDY: The aim of this study was to evaluate the safety of CGHD by conducting acute toxicity and long-term toxicity experiments, with the objective of providing evidence for its clinical safety and a theoretical foundation for its clinical application. MATERIALS AND METHODS: KM mice were selected for the acute toxicity experiment and were administered water or CGHD-E 3 times within 24 h. The reactions of the animals to CGHD treatment were observed and recorded within 1 h after administration and then once a day for 14 consecutive days. SD rats were selected to conduct the long-term toxicity experiment. The drug-treated groups were administered different doses of CGHD-E, which were equivalent to 10 times, 20 times and 50 times the clinical dose in humans. The rats were administered the drug for 28 consecutive days. After 28 days, the animals were sacrificed, and routine blood tests, blood coagulation function analysis, liver and kidney function tests, and glycolipid metabolism related tests were conducted. The major organs of the rats were collected to calculate organ coefficients and perform hematoxylin-eosin (HE) staining. RESULTS: In the CGHD-E acute toxicity experiment, the drug-treated groups did not show adverse reactions or poisoning symptoms, and the maximum tolerated dose of CGHD-E in mice was greater than 45.072 g/kg. In the long-term toxicity experiment, drug-treated rats generally exhibited a good condition, but continuous administration decreased on body weight and food intake, especially in male rats. Coagulation function alterations and the impact on the liver during long-term drug administration were also assessed, which should be emphasized in clinical applications. No significant toxic effects were observed according to routine blood tests or test of liver and kidney function, glucose and lipid metabolism, or ion metabolism. CONCLUSIONS: The results of this study showed that CGHD was nontoxic or had low toxicity, providing not only a scientific basis for its clinical application, determining the appropriate clinical dose and monitoring clinical toxicity but also theoretical support for subsequent clinical drug trials.

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.

The effect of local treatment modalities in patients with early-stage adenocarcinoma of the uterine cervix: A population-based analysis.

BACKGROUND: To determine the optimal local treatment modalities in stage IB-IIA adenocarcinoma (AC) of the uterine cervix and assess the impact of tumor size in the clinical outcomes. METHODS: Patients with a primary diagnosis of stage IB-IIA cervical AC between 1988 and 2013 were identified using the Surveillance, Epidemiology, and End Results database. Cox regression analyses was performed to analyze the effect of local treatment modalities on cause-specific survival (CSS) and overall survival (OS). RESULTS: A total of 2773 patients were identified. Of these, 1816, 795, and 162 patients received primary surgery, surgery and radiotherapy (RT), and primary RT, respectively. Local treatment modality was the independent prognostic factor for CSS and OS. Patients who received primary surgery had better CSS and OS, especially in patients with tumor size ≤4 cm. However, of those with tumor size >4 cm, patients who underwent primary surgery showed significantly better survival; the survival of patients who underwent surgery and RT was not significantly different from those who underwent primary RT alone. The results were not influenced by the year before (1988-1999) and after (2000-2013) the era of concurrent chemoradiation therapy. CONCLUSIONS: Surgery remains the optimal local treatment modality in patients with early stage cervical AC.