Attenuated LKB1-SIK1 signaling promotes epithelial-mesenchymal transition and radioresistance of non–small cell lung cancer cells

Abstract

Background

Radiotherapy is one of the main therapeutic approaches for non–small cell lung cancer (NSCLC). However, radioresistant cancer cells can eventually cause tumor relapse and even fatal metastasis. It is thought that radioresistance and metastasis could be potentially linked by epithelial-mesenchymal transition (EMT). In this study, we established radioresistant NSCLC cells to investigate the potential relationship among radioresistance, EMT, and enhanced metastatic potential and the underlying mechanism involving liver kinase B1 (LKB1)-Salt-inducible kinase 1 (SIK1) signaling.

Methods

The radioresistant cell lines A549R and H1299R were generated by dose-gradient irradiation of the parental A549 and H1299 cells. The radioresistance/sensitivity was evaluated by Cell Counting Kit-8 assay, apoptosis analysis, and/or clonogenic cell survival assay. The EMT phenotype and the signaling change were assessed by Western blotting. The abilities of invasion and migration were evaluated by transwell assays and wound healing assays.

Results

The radioresistant cell lines A549R and H1299R displayed mesenchymal features with enhanced invasion and migration. Mechanistically, A549R and H1299R cells had attenuated LKB1-SIK1 signaling, which leaded to the up-regulation of Zinc-finger E-box-binding homeobox factor 1 (ZEB1)—a transcription factor that drives EMT. Re-expression of LKB1 in A549R cells reversed the EMT phenotype, whereas knockdown of LKB1 in H1299R cells further promoted the EMT phenotype. Moreover, re-expression of LKB1 in A549 cells increased the radiosensitivity, whereas knockdown of LKB1 in H1299 cells decreased the radiosensitivity.

Conclusions

Our findings suggest that attenuated LKB1-SIK1 signaling promotes EMT and radioresistance of NSCLC cells, which subsequently contributes to the enhanced metastatic potential. Targeting the LKB1-SIK1-ZEB1 pathway to suppress EMT might provide therapeutic benefits.

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Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer

Abstract

Background

Androgen insensitivity syndrome (AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor (AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer (CRC) have been described.

Case presentation

Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a microRNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers.

Conclusions

By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.

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Reporting adverse events in cancer surgery randomized trials: a systematic review of published trials in oesophago-gastric and gynecological cancer patients

Publication date: Available online 7 June 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Leila Meghelli, Fabrice Narducci, Christophe Mariette, Guillaume Piessen, Marie Vanseymortier, Eric Leblanc, Pierre Collinet, Alain Duhamel, Nicolas Penel
BackgroundFew reports describe how adverse events (AEs) are reported in cancer surgery trials.Materials and MethodsWe systematically reviewed 179 consecutive study reports issued between January 1, 1990 and November 15, 2014, which investigated surgery in oesophago-gastric (OG) or gynecologic (GY) cancer patients. Based on the reviewed reports, we assessed how AEs were reported according to CONSORT statement.ResultsMorbidity assessment was the primary objective of 56 studies (31.3%). Postoperative AEs were described in 161 studies (90%). Definition of AEs and grading scale (NCI-CTC AE, Dindo-Clavien scale, etc …) were given in 27.3% and 16.8% of studies, respectively. AEs were reported by event and grade in 8.3% of studies. Definition of expectedness, seriousness, causality and safety population were present in 0.5%, 1.1%, 7.8%, and 7.2% of the studies, respectively. Reporting of AEs did not improve over time nor better in high-impact factor journals.ConclusionThe reporting of AEs in cancer trials investigating surgery needs to be improved.



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Adenosquamous Carcinoma of the Duodenum: a Rare Entity

Abstract

Adenosquamous carcinomas (ASC) of the duodenum are extremely rare neoplasms. They have been reported throughout gastrointestinal tract, including the gastroesophageal junction and the anal canal. Only a few cases of ASC of the small bowel and duodenum have been reported in the literature. Here in we report a case ASC of the second part of the duodenum in a 78-year-old man.

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Sarcomatoid Carcinoma of the Penis

Abstract

Sarcomatoid carcinomas are biphasic tumours, which occur at any site in the human body. It rarely affects the penis, with only 38 cases being reported in literature. It may be considered as a variant of squamous cell carcinoma or a dedifferentiated tumour. We report a 60-year old gentleman who presented with a swelling in the glans penis. He underwent a partial penectomy. Histopathology revealed sarcomatoid carcinoma of the penis, which was confirmed by immunohistochemistry. The rarity of this clinical entity makes its diagnosis difficult.

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Oncological Safety of Breast Conservation Surgery in Young Females

Abstract

Breast conservation surgery (BCS) is the standard of care in early breast cancer. The oncological safety of this procedure has been proven beyond doubt in several randomised control trials. But there are concerns regarding the safety of this procedure in young females. The concern is regarding increased risk of local recurrence. This issue has not been addressed in any major trial. In this prospective study we intend to look into the oncological safety of BCS in young patients who are less than forty years of age.

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Deep Vein Thrombosis in Indian Cancer Patients Undergoing Major Thoracic and Abdomino-Pelvic Surgery

Abstract

The aim of the study was to determine the incidence of postoperative deep vein thrombosis (DVT) in Indian patients undergoing surgery for thoracic and abdomino-pelvic malignancies.

A prospective observational study was conducted in a tertiary care cancer centre in North India. Two hundred and fifty consecutive patients who underwent curative surgery for thoracic and abdomino-pelvic malignancies during the period March 2014 to March 2015 were enrolled in the study. Perioperative pharmacological antithrombotic prophylaxis was not prescribed to any of the patient as per the institutional protocol. All the patients underwent colour duplex ultrasound of the bilateral lower limbs – preoperatively to determine the baseline status, and on 7th and 28th day postoperatively to look for presence of DVT. None of the patient in the study cohort showed clinical or radiological evidence of lower limb deep vein thrombosis. Our study suggests very low incidence of deep vein thrombosis in Indian patients undergoing surgery for thoracic and abdomino-pelvic malignancy.

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