Connexin 32 downregulation is critical for chemoresistance in oxaliplatin-resistant HCC cells associated with EMT.

Background: Oxaliplatin (OXA)-based chemotherapy is critical in the management of advanced hepatocellular carcinoma (HCC); however, acquired drug resistance has largely restricted its clinical efficacy. This study aims to explore the key mechanisms and regulatory factors determining chemosensitivity in HCC. Methods: We developed OXA-resistant (OR) HCC cells and used multiple methods, including real-time RT-PCR, Western blot, immunofluorescence, transwell invasion assay, wound-healing assay, MTT assay, gene transfection, and immunohistochemistry to achieve our goals. Results: We found that OR HCC cells showed a typical epithelial-mesenchymal transition (EMT) phenotype. Meanwhile, the expression of Cx32, a major member of the liver connexin (Cx) family, was lowly expressed in OR HCC cells. Downregulation of Cx32 in parental HCC cells led to EMT induction and thereby reduced OXA cytotoxicity, while Cx32 upregulation in OR HCC cells could reverse the EMT phenotype and partially restore chemosensitivity to OXA. Finally, in human HCC tissue samples, Cx32 was positively correlated with the expression of the EMT marker E-cadherin and negatively correlated with the expression of Vimentin. Conclusion: Our findings demonstrated that downregulation of Cx32 may be an important determinant for HCC cells to acquire EMT-related acquired drug resistance to OXA, and targeting Cx32 could be a novel strategy to overcome OXA resistance in HCC.

AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells.

Colorectal cancer (CRC) causes significant mortalities worldwide. Fibroblast growth factor (FGF) receptor (FGFR) signaling is frequently dysregulated and/or constitutively activated in CRCs, contributing to cancer carcinogenesis and progression. Here, we studied the activity of AZD-4547, a novel and potent FGFR kinase inhibitor, on CRC cells. AZD-4547 inhibited CRC cell growth in vitro, and its activity correlated with the FGFR-1/2 expression level. AZD-4547 was cytotoxic and pro-apoptotic in FGFR-1/2-expressed CRC cell lines (NCI-H716 and HCT-116), but not in FGFR-1/2 null HT-29 cells. Further, AZD-4547 inhibited cell cycle progression and attenuated the activation of FGFR1-FGFR substrate 2 (FRS-2), ERK/mitogen-activated protein kinase (MAPK), and AKT/mammalian target of rapamycin (AKT/mTOR) signalings in NCI-H716 and HCT-116 cells. In vivo, AZD-4547 oral administration at effective doses inhibited NCI-H716 (high FGFR-1/2 expression) xenograft growth in nude mice. Phosphorylation of FGFR-1, AKT, and ERK1/2 in xenograft specimens was also inhibited by AZD-4547 administration. Thus, our preclinical studies strongly support possible clinical investigations of AZD-4547 for the treatment of CRCs harboring deregulated FGFR signalings.

[Efficacy of modified radical operation of preserving nipple-areolar complex on early stage breast cancer].

BACKGROUND AND OBJECTIVE: Modified radical mastectomy of preserving nipple-areolar complex (NAC) is an important surgical therapy for stage I-IIa breast cancer, but the oncological risk is controversial. This study was to compare the efficacy of NAC-preserving modified radical operation and conventional modified radical operation on early stage breast cancer. METHODS: The patients who received NAC-preserving modified radical operation (42 patients) or conventional modified radical operation (84 patients) from January 1998 to December 2003 in the First Affiliated Hospital of Bengbu Medical College were matched with a ratio of 1:2 by age at diagnosis, axillary lymph node status, sexual hormone receptor status, tumor size and Her-2/neu expression for retrospective analysis. The loco-regional recurrence, distant metastasis, 5-year disease-free survival (DFS) and 5-year overall survival (OS) between the two groups were compared. RESULTS: Median follow-up time was 48 months in NAC-preserving operation group and 44 months in conventional operation group. The 5-year occurrence rate of loco-regional recurrence was 2.44% in NAC-preserving operation group and 3.21% in conventional operation group (P=0.771). The 5-year occurrence rate of distant metastasis was 5.64% in NAC-preserving operation group and 4.30% in conventional operation group (P=0.654). The 5-year OS rates were 96.00% in NAC-preserving operation group and 98.18% in conventional operation group (P=0.694). The 5-year DFS rates were 91.67% in NAC-preserving operation group and 92.26% in conventional operation group (P=0.597). CONCLUSION: Modified NAC-preserving radical operation results in the same effect on early stage breast cancer as conventional modified radical operation based on careful consideration of the indications, and results in better cosmetic appearance after restitution and better quality of life.

[Clinicopathologic analysis of the nipple-areolar complex occult involvement in early stage breast carcinoma].

OBJECTIVE: The aim of this study was to investigate the incidence of nipple-areola complex (NAG) involvement in stage I - II a breast cancer patients who underwent skin-sparing mastectomy and to determine the associated risk factors, to provide a theoretical basis for modified radical mastectomy preserving NAC and breast reconstruction in early stage breast cancer patients. METHODS: A total of 68 women with primary breast cancer were included in this study. The following associated risk factors of NAC involvement were assessed and compared with those of non-involvement: the distance from the tumor site to the edge of areola (D), axillary lymph node status, over-expression of HER-2/neu, location of tumor, TNM stage, abnormal nipple (nipple indentation, erosion, discharge), tumor size, age, histological type, as well as status of estrogen receptor (ER) and progesterone receptor (PR), by Chi-square test. RESULTS: The positive rate of NAG involvement was 13.2%. It decreased with an increase in the distance from the tumor site to the edge of the areola (D) (chi2 = 10.68, P <0.01)), and higher incidence of NAG involvement was found in patients with axillary lymph node metastasis (chi2 = 14. 61, P < 0.01) and over-expression of HER-2/neu (chi2 =6.83, P <0.01). Location of tumor (P <0.01), TNM stage (chi2 =3.85, P <0.05), abnormal nipple (chi2 = 11.65, P<0.01), and tumor size (chi2 =4.13, P <0.05) also had influence on the NAG involvement. No significant correlation between NAC involvement and age (P > 0.05)), histological type (chi2 = 0.07, P > 0.05)), as well as status of estrogen receptor (ER) (chi2 = 0.06, P > 0.05) and progesterone receptor (PR) (chi2 = 0.04, P > 0.05) was found. Most of the NAG involvement was caused by ductal infiltration. CONCLUSION: In the stage I - II a breast cancer patients, location of tumor, TNM stage, the distance from the tumor site to the edge of areola (D), abnormal nipple, over-expression of HER-2 and metastases in axillary lymph nodes are the primary influential factors of NAG involvement.