Zhixun Zhao

Role of MicroRNA 30a Targeting Insulin Receptor Substrate 2 in Colorectal Tumorigenesis

ABSTRACT MicroRNAs (miRNAs) are dysregulated in many types of malignant diseases, including colorectal cancer. miRNA 30a (miR-30a) is a member of the miR-30 family and has been implicated in many types of cancers. In this study, we determined the expression of miR-30a in human colon cancer tissues and cell lines. miR-30a was found to be significantly downregulated in both the tissues and cell lines. Furthermore, overexpression of miR-30a inhibited, while silencing of miR-30a promoted, cell proliferation, migration, and invasion in vitro. Consistently, stable overexpression of miR-30a suppressed the growth of colon cancer cell xenografts in vivo. Moreover, bioinformatic algorithms and luciferase reporter assays revealed that insulin receptor substrate 2 (IRS2) is a direct target of miR-30a. Further functional studies suggested that repression of IRS2 by miR-30a partially mediated the tumor suppressor effect of miR-30a. In addition, miR-30a inhibited constitutive phosphorylation of Akt by targeting IRS2. Additionally, clinicopathological analysis indicated that miR-30a has an inverse correlation with the staging in patients with colon cancer. Taken together, our study provides the first evidence that miR-30a suppressed colon cancer cell growth through inhibition of IRS2. Thus, miR-30a might serve as a promising therapeutic strategy for colon cancer treatment.

Exploration of the Optimal Minimum Lymph Node Count after Colon Cancer Resection for Patients Aged 80 Years and Older

The elderly colon cancer (CC) patients are increasing and represent a heterogeneous patient group. The objectives of this study were to identify the features of lymph node examination and to explore the optimal minimum lymph node count after CC resection for patients aged ≥80. Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 65719 CC patients in stage I-III between 2004 and 2012, 26.0% of patients were aged ≥80. The median node count decreased with increasing age, which were 25.5, 20.2, 17.8 and 16.9 for patients aged 20–39, 40–59, 60–79, and ≥80. The rate of ≥12 nodes and the rate of node positivity for patients aged ≥80 were obviously lower than younger patients. Using X-tile analysis, we determined 9 nodes as the optimal node count for patients aged ≥80. Then, we compared the 5-year cancer specific survival (CSS) between patients with ≥9 nodes and <9 nodes. The results showed the 5-year CSSs were improved for patients with ≥9 nodes. Furthermore, the rate of node positivity and survival under the 9-node measure were equal to 12-node measure. Therefore, the lymph node examination should be discriminately evaluated for elder patients, and 9-node measure was available for patients aged ≥80.

The Incidence Characteristics of Second Primary Malignancy after Diagnosis of Primary Colon and Rectal Cancer: A Population Based Study

Background With the expanding population of colorectal cancer (CRC) survivors in the United States, one concerning issue is the risk of developing second primary malignancies (SPMs) for these CRC survivors. The present study attempts to identify the incidence characteristics of SPMs after diagnosis of first primary colon cancer (CC) and rectal cancer (RC). Methods 189,890 CC and 83,802 RC cases were identified from Surveillance, Epidemiology and End Results Program (SEER) database. We performed rate analysis on incidence trend of SPMs in both CC and RC. Expected incidence rates were stratified by age, race and stage, calendar year of first CRC diagnosis and latency period since first CRC diagnosis. The standardized incidence ratios (SIRs), measure for estimating risk of SPMs, were calculated for CC and RC respectively. Results The trends of incidence of SPMs in both CC and RC were decreasing from 1992 to 2012. Both CC and RC survivors had higher risk of developing SPMs (SIRCC = 1.13; SIRRC = 1.05). For CC patients, the highest risks of SPM were cancers of small intestine (SIR = 4.03), colon (SIR = 1.87) and rectum (SIR = 1.80). For RC patients, the highest risks of SPMs were cancers of rectum (SIR = 2.88), small intestine (SIR = 2.16) and thyroid (SIR = 1.46). According to stratified analyses, we also identified incidence characteristics which were contributed to higher risk of developing SPMs, including the age between 20 and 40, American Indian/Alaska Native, localized stage, diagnosed at calendar year from 2002 to 2012 and the latency between 12 and 59 months. Conclusions Both CC and RC survivors remain at higher risk of developing SPMs. The identification of incidence characteristics of SPMs is extremely essential for continuous cancer surveillance among CRC survivors.

Radiotherapy dose led to a substantial prolongation of survival in patients with locally advanced rectosigmoid junction cancer: a large population based study

Radiotherapy is widely applied for locally advanced rectal cancer (RC) to improve both local control and long-term outcomes. However, the efficacy of radiotherapy for rectosigmoid junction cancer (RSC) is still undetermined. Here, we identified 10074 patients who were diagnosed with locally advanced RSC from Surveillance, Epidemiology, and End-Results (SEER) cancer registry. These patients were divided into three subgroups according to different therapy strategies, including surgery alone, surgery plus preoperative radiotherapy and surgery plus postoperative radiotherapy. 5-year cancer-specific survival (CSS) and 5-year overall survival (OS) were obtained. Kaplan–Meier methods and Cox regression models were used to estimate the correlations between prognostic factors and survival outcomes. The 5-year CSSs for RSC patients treated with pre- and postoperative radiotherapy were 72.3% and 72.2%, which were significantly higher than surgery alone (64.8%). The 5-year OSs for RSC patients treated with pre- and postoperative radiotherapy were 71.6% and 71.2%, which were higher than surgery alone (64.0%). In the separate analyses of stage II and III RSC patients, the similar trends were also obtained. In addition, pre- and postoperative radiotherapy were equally identified as valuable prognostic factors for better survival outcomes in RSC patients. Furthermore, the results following propensity score matching also confirmed that the long-term survivals of RSC patients were improved following radiotherapy. In conclusion, locally advanced RSCpatients could obtain potential long-term survival benefits from radiotherapy. A prospective randomized control trial should be performed to further validate the strength of evidence in current study.

Whether regional lymph nodes evaluation should be equally required for both right and left colon cancer

Despite the adequacy of nodal evaluation was gradually improved for colon cancer, the disparity in nodal examination for right colon cancer (RCC) and left colon cancer (LCC) still begs the question of whether 12 nodes is an appropriate threshold for both RCC and LCC. From Surveillance, Epidemiology, and End-Results (SEER) database, we identified 53897 RCC patients and 11822 LCC patients. Compared with LCC patients, RCC patients examined more lymph nodes (18.7 vs 16.3), and more likely to examine ≥12 nodes (P<0.001), whereas RCC patients showed lower rates of node positivity (P<0.001). To balance the nodal disparity between RCC and LCC, we revised the 12-node measure based on different tumor locations. With the X-tile, we determined 15 as the optimal node number for RCC and 11 for LCC. To validate the availability of this revised nodal evaluation, the 5-year cancer specific survival (CSS) was calculated according to the optimal node number in RCC and LCC patients, Coxs regression model were used to further assess the prognostic value of this revised nodal evaluation. The results showed that 5-year CSSs were significantly improved for RCC patients with ≥15 lymph nodes, and also for LCC patients with ≥11 lymph nodes (P<0.001). This revised nodal evaluation could also improve the rate of nodal positivity and long-term survival in both RCC and LCC patients compared with 12-node measure. Therefore, the lymph node examination should be discriminately evaluated for RCC and LCC, instead of using 12-node measure to colon cancer as a whole.

GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer

GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and evaluate the clinical value of GADD45B in stage II colorectal cancer (CRC). The expression patterns and prognostic value of GADD45B in CRC were analyzed based on The Cancer Genomic Atlas (TCGA). GADD45B expression features of 306 patients with stage II CRC and 201 patients with liver metastasis of CRC were investigated using immunochemical staining on tissue microarrays. Afterward, survival analysis and stratification analysis were performed in stage II to explore the prognostic and predictive significance of GADD45B. Overexpressed GADD45B is associated with poorer prognosis for CRC patients both in overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p = 0.001) based on the TCGA database. Analysis results according to the stage II CRC cohort and the liver metastatic CRC cohort revealed that GADD45B was gradually upregulated in normal mucosa including primary colorectal cancer (PCC). Colorectal liver metastases (CLM) tissues were arranged in order (normal tissue vs. PCC p = 0.005 and PCC vs. CLM p = 0.001). The low GADD45B group had a significantly longer five-year OS (p = 0.001) and progression-free survival (PFS) (p < 0.001) than the high GADD45B group for the stage II patients. The multivariate Cox regression analysis results proved that the expression level of GADD45B was an independent prognostic factor for stage II after radical surgery (OS: Hazard Ratio (HR) 0.479, [95% confidence interval (CI) 0.305–0.753] and PFS:HR 0.490, [95% CI 0.336–0.714]). In high GADD45B expression subgroup of stage II cohort, the patients who underwent adjuvant chemotherapy had longer PFS than those who did not (p = 0.008). High expression levels of GADD45B is an independent prognostic factor of decreased OS and PFS in stage II CRC patients. The stage II CRC patients with high GADD45B expression might benefit from adjuvant chemotherapy.

Comparison of long-term outcome between hemicolectomy and partial colectomy in the elderly: a large population-based study

Due to large progress has been achieved in surgical techniques, anesthesia and perioperative care, it is accepted that the very elderly colon cancer (CC) patient is not contraindication for surgery. However, it is a controversy that an extended or a less aggressive surgical approach should be performed for this population. Here, we identified 28110 CC patients aged ≥80 from Surveillance, Epidemiology, and End-Results (SEER) database. The surgical approaches included extended hemicolectomy (HC) and partial colectomy (PC). 5-year cancer specific survival (CSS) was obtained. Kaplan–Meier methods and Cox regression models were used to assess the correlations between prognostic factors and long-term survival. The 5-year CSS for patients treated with HC were 45.6%, which were similar to patients who received PC (44.8%), the survival difference has no statistical significance (P=0.087). The result following propensity score matching further confirmed long-term survival were equal between HC and PC. However, patients in AJCC T3/T4 stage and with tumor size ≥5cm could obtain survival benefit from the extended surgery. In conclusion, most of elderly CC patients could not obtain survival benefit from extended resection. Partial colectomy should also be considered as an alternative approach for this group of patients.Due to large progress has been achieved in surgical techniques, anesthesia and perioperative care, it is accepted that the very elderly colon cancer (CC) patient is not contraindication for surgery. However, it is a controversy that an extended or a less aggressive surgical approach should be performed for this population. Here, we identified 28110 CC patients aged ≥80 from Surveillance, Epidemiology, and End-Results (SEER) database. The surgical approaches included extended hemicolectomy (HC) and partial colectomy (PC). 5-year cancer specific survival (CSS) was obtained. Kaplan-Meier methods and Cox regression models were used to assess the correlations between prognostic factors and long-term survival. The 5-year CSS for patients treated with HC were 45.6%, which were similar to patients who received PC (44.8%), the survival difference has no statistical significance (P=0.087). The result following propensity score matching further confirmed long-term survival were equal between HC and PC. However, patients in AJCC T3/T4 stage and with tumor size ≥5cm could obtain survival benefit from the extended surgery. In conclusion, most of elderly CC patients could not obtain survival benefit from extended resection. Partial colectomy should also be considered as an alternative approach for this group of patients.

Polymorphisms in the CHIT1 gene: Associations with colorectal cancer

Colorectal cancer (CRC) is one of the most common solid tumors worldwide, often associated with inflammation. The microbes in the human intestine have a key role in inflammations and CRC. Chitotriose renders growth advantage to some bacteria, especially some pathogens, and thus has a role in inflammations. The enzyme chitotriosidase, encoded by the CHIT1 gene of the host, may degrade chitotriose with different efficiencies depending on the alleles. We sequenced the CHIT1 gene for 320 Chinese Han CRC patients and 404 normal controls, and focused on variations rs61745299 and rs35920428 within the CHIT1 gene for their possible roles in CRC. Statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 19.0). Multiple sequence alignment was conducted using the Vector NTI, and protein expression levels were analyzed by western blotting. The two variations, rs61745299 and rs35920428 within the CDS region of CHIT1 gene, were associated with the risk of CRC (both with P values < 0.001). Western blotting analysis showed that the variations increased the expression levels of the CHIT1 and C-reaction protein genes in the cancer tissue. We conclude that the two variations of CHIT1, rs61745299 and rs35920428, increase expression of the gene and are associated with CRC in Chinese Han populations.

Prevention and Treatment of Common Complications of NOSES in Colorectal Cancer

As a surgical technique, NOSES is unique in digestive tract reconstruction and extraction but is otherwise similar to open and conventional laparoscopic surgery in terms of surgical complications. In this chapter, we discuss the causes, clinical manifestations, and management of complications associated with colorectal surgery.

Abnormal Liver Function Induced by Space-Occupying Lesions Is Associated with Unfavorable Oncologic Outcome in Patients with Colorectal Cancer Liver Metastases

An early prediction of prognosis for patients with colorectal liver metastasis (CRLM) may help us determine treatment strategies. Liver function reflects the effect of the overall metastatic burden. We investigated the prognostic value of liver function in CRLM patients. In our study, patients with abnormal LFTs (liver function tests) had a poorer prognosis than did those with normal LFTs (P < 0.05). A multivariate analysis revealed that LFTs was an independent prognostic factor for CRLM. For those patients with abnormal LFTs, novel prognostic contour maps were generated using LFTs, and no positive correlation exists between the values of survival duration and abnormal LFTs. Additionally, the MTVR (metastatic tumor volume ratio) was measured directly by magnetic resonance imaging and was shown to be highly correlated to LFTs by a Pearson correlation analysis. A multivariate logistic regression analysis also demonstrated that the MTVR and hepatectomy were independently predictive of abnormal LFTs. The space-occupying effect of metastatic lesions can cause abnormal LFTs, resulting in a poor prognosis. Biochemical analyses of LFTs at the initial diagnosis of CRLM enable the stratification of patients into low- and high-risk groups; it may help clinicians determine promising treatment strategies.