Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of “client” proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail.

Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach

Heat shock proteins (HSP) are a subset of the molecular chaperones, best known for their rapid and abundant induction by stress. HSP genes are activated at the transcriptional level by heat shock transcription factor 1 (HSF1). During the progression of many types of cancer, this heat shock transcriptional regulon becomes co-opted by mechanisms that are currently unclear, although evidently triggered in the emerging tumor cell. Concerted activation of HSF1 and the accumulation of HSPs then participate in many of the traits that permit the malignant phenotype. Thus, cancers of many histologies exhibit activated HSF1 and increased HSP levels that may help to deter tumor suppression and evade therapy in the clinic. We review here the extensive work that has been carried out and is still in progress aimed at (1) understanding the oncogenic mechanisms by which HSP genes are switched on, (2) determining the roles of HSF1/HSP in malignant transformation and (3) discovering approaches to therapy based on disrupting the influence of the HSF1-controlled transcriptome in cancer.

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Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update

Small heat shock proteins in cancer therapy and prognosis.

miR-203 reverses chemoresistance in p53-mutated colon cancer cells through downregulation of Akt2 expression

Chemoresistance is a key cause of treatment failure in colon cancer. MiR-22 is a tumor-suppressing microRNA. To explore whether miR-22 is an important player in the development of chemoresistance in colon cancer, we overexpressed miR-22 and subsequently tested its role in cell proliferation, apoptosis, survival, and associated signaling in p53-mutated HT-29 and HCT-15 cells, and p53 wild-type HCT-116 cells. We further investigated the role of miR-22 on cytotoxicity of paclitaxel in both the p53-mutated and p53 wild-type colon cancer cells. Results showed that HT-29 and HCT-15 cells were resistant to paclitaxel-induced cytotoxicity, which normally inhibits cell proliferation and survival, and induces apoptosis. Conversely, HCT-116 was relatively sensitive to the cytotoxicity of paclitaxel. Overexpression of miR-22 significantly decreased cell proliferation and survival, and induced cell apoptosis in the p53-mutated colon cancer cells, but played no role in the p53 wild-type cells. Importantly, miR-22 overexpression enhanced the cytotoxic role of paclitaxel in p53-mutated HT-29 and HCT-15 cells, but not in p53 wild-type HCT-116 cell. We further demonstrated that the tumor-suppressive role of miR-22 in p53-mutated colon cancer cells was mediated by upregulating PTEN expression, which negatively regulated Akt phosphorylation at Ser(473) and MTDH expression, and subsequently increased Bax and active caspase-3 levels. Our study is the first to identify the tumor-suppressive role of miR-22 and its associated signaling in the p53-mutated colon cancer cells and highlighted the chemosensitive role of miR-22.

Overexpression of miR-22 reverses paclitaxel-induced chemoresistance through activation of PTEN signaling in p53-mutated colon cancer cells.

AIM: To determine the basic demographic features of colorectal cancer (CRC) in five hospitals located in four different areas of Guangdong Province, China.

METHODS: A review of patient records from 1986 to 2006 from five hospitals was conducted. Patient data was obtained, including age, gender, location of lesions, staging and histological type of CRC. The Chi-square test was used to assess differences in rates and a significance level of 0.05 was used. Univariate comparisons were made via Fisher’s exact tests.

RESULTS: Analysis was carried out on 8172 CRC patents, 6.1% (499/8172) of the patients were aged ≤ 30 years. The peak incidence was between the ages 61-70 years (27.8%). The mean age at CRC diagnosis increased from 52 years (1986-1988) to 60 years (2004-2006) and the proportion of young CRC patients decreased from 8.0% to 5.9% over the same period. Of 8172 lesions, 4434 (54.3%) were located in rectum and 3738 (45.7%) in colon. The incidence of rectal cancer decreased significantly from 59.4% (1989-1991) to 51.8% (2004-2006) and right sided colon cancer increased from 40.6% to 48.2%. The mean age, anatomic distribution, histological type and differentiation degree were significantly different among the four geographical areas (P < 0.05).

CONCLUSION: The hospitalization rate for CRC has increased in Guangdong in recent years. The characteristics of CRC from the five hospitals located in the four different areas of Guangdong Province are also different. Further studies are needed to assess more recent trend in the incidence and prevalence of CRC as well as the respective roles of genetic and environmental factors in CRC.

Colorectal cancer in Guangdong Province of China: A demographic and anatomic survey

The heat shock protein 27-kDa (HSP27) has been found overexpressed in several types of human cancer and is associated with treatment resistance and poor prognosis. Recent proteomic studies demonstrate that HSP27 is significantly overexpressed in colorectal cancer (CRC). However, the relationship between HSP27 expression and patient prognosis remains nascent. In the present study, we aimed to investigate the expression of HSP27 and its correlation with clinicopathological parameters in CRC patients. Dysregulated expression of HSP27 was observed in neoplastic lesions, and appears to be involved in disease progression. Immunohistochemical analysis showed that detectable HSP27 expression was found in 145/182 (79.7%) CRC cases. There was a significant correlation between HSP27 expression and TNM stage (P=0.003). Patients with low HSP27 expression had better survival than those with high HSP27 expression. Additionally, multivariate analysis indicated that HSP27 expression is an independent prognostic marker for CRC. These results suggest that elevated expression of HSP27 protein is a frequent event during the progression of CRC. HSP27 might be used as a valuable prognostic marker for patients with CRC.

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Clinical significance of HSP27 expression in colorectal cancer.

OBJECTIVE To study the trend of clinical characteristics of colorectal cancer during the past 20 years in Gaungdong province. METHODS The clinical data of 3870 cases of colorectal cancers confirmed pathologically who were hospitalized to Nanfang Hospital and Huizhou Municipal Hospital, Guangdong province, 1985 - 2004 were divided into 5-year groups and analyzed. RESULTS The hospitalization number of colorectal cancer in the 2000 - 20004 5-year period was 102%, higher than that of the 1985 - 1989 period with an annual increase of 5.1%. The median age of incidence 2000 - 2004 was 58.6 years, 8.4 years higher than that in 1985 - 1989. The male to female ratio of the 3870 patients was 1.42:1. The male to female ratio 2000 - 2004 was 1.35:1, lower than that 1985 - 1989 (1.50:1). The proportion of rectal cancer 2000 - 2004 was 49.7%, significantly lower than that in 1985 - 1989 (64.8%), while the proportion of right hemi-colon cancer 2000 - 2004 was 28.7%, significantly higher than that in 1985 - 1989 (18.0%). The proportion of moderately and well differentiated cancer 2000 - 2004 was 80.6%, higher than that in 1985 - 1989 (70.1%), and the proportion of poorly differentiated cancer 2000 - 2004 was 19.4%, lower than that in 1985 - 1989 (29.9%). The proportion of colorectal cancer at Dukes A stage 2000 - 2004 was 9.8%, higher than that in 1985 - 1989 (3.2%). CONCLUSION In the past 20 years, the incidence of colorectal cancer has increased in Guangdong province with a n increase of median age of incidence, The male to female ratio has decreased, and the incidence of right hemi-colon cancer, the rates of higher differentiated cancer and Dukes A stage cancer have increased.

The trend of clinical characteristics of colorectal cancer during the past 20 years in Guangdong province

OBJECTIVE To explore the clinical characteristics and pattern of incidence of colorectal cancers in Guangdong region METHODS Analysis and summary were made for 3870 colorectal cancer patients pathologically confirmed in the Nanfang Hospital and Huizhou Municipal Central Hospital of Guangdong province RESULTS Median age of 3870 cases with colorectal cancer was 553 The high-risk age ranged from 41 to 70204 cases among them were young patients (age < or = 30, 53%) With increase of age the number of cases with rectal cancers decreased gradually, while cancers occurring in the right hemi colon increased gradually The ratio between male and female was 142:1 There were altogether 3958 colonic cancer lesions found in all the cases Among them 3783 (978%) cases presented with a single lesson, 87 (22%) cases presented with multiple lesions 2243 (567%) lesions located in the rectum, 717 (181%) in the left hemi colon, 998 (252%) in the right hemi colon Histological types in all the lesions cases were grouped as follows: tubular adenocarcinoma 2943 (760%); papillary adenocarcinoma 256 (66%); mucinous carcinoma 425 (110%); and miscellaneous types 246 (64%) Colorectal cancers with poor differentiation occurring in the young were 382% while in the middle age and the elderly were 299% and 146%, respectively The difference between two groups showed a statistical significance (P < 001) The cases with confirmed stage A, B, C and D were 234 (60%), 1936 (500%), 1310 (339%) and 390 (101%), respectively, according to Dukes' staging system The cases with the progressing stages (B, C, D stages) were 3636 (940%) among all the cases CONCLUSIONS The number of patients with colorectal cancer admitted in hospital increased gradually in the recent 20 years, and showed a trend with the decrease percentage in rectal cancer and the gradual increasing in right hemi colon cancer with increase of patients age Half of the colorectal cancer occurred in the rectum, the rest occurred in the left and right hemi colon The three clinical epidemiological characteristics of colorectal cancer, which once existed in Chinese, has disappeared in Guangdong region

Clinical epidemiological characteristics of 3870 cases of colorectal cancers in Guangdong region

OBJECTIVE To explore the epidemiology characteristics of colorectal cancer on community group in Guangdong province. METHODS Huidong was took as the research spot to investigate the sickness and incidence of colorectal cancer among a whole community group in Guangdong province, and two projects were used simultaneously: "screening of colorectal cancer in high risk group" and "screening project using fecal occult blood test". The numeration time for population of 10 towns was set at July 1, 2005. Five towns were sampled out from Huidong with 100,859 persons. Meanwhile, the diseases and death cause registering system was established. RESULTS The incidence of colorectal cancer in Huidong community group was 15.2/100,000 (male 17.2/100,000, female 13.0/100,000), the age-adjusted incidence was 17.6/100,000 (male 19.5/100,000, female 16.7/100,000). The morbidity was 41.9/100,000 (male 46.5/100,000, female 37.2/100,000), the age-adjusted morbidity was 49.0/100,000 (male 54.1/100,000, female 45.6/100,000). The mortality was 5.0/100,000 (male 5.9/100,000, female 4.0/100,000) and the age-adjusted morbidity was 6.4/100,000 (male 7.2/100,000, female 5.7/100,000). CONCLUSION The incidence of colorectal cancer in Huidong community group is lower than that of high incidence area in China, but gets close to the normal incidence area of China and general level of the world.

Xu-hui Zhong

Papers

Colorectal cancer in Guangdong Province of China: A demographic and anatomic survey

Clinical significance of HSP27 expression in colorectal cancer.

The trend of clinical characteristics of colorectal cancer during the past 20 years in Guangdong province

Clinical epidemiological characteristics of 3870 cases of colorectal cancers in Guangdong region

Epidemiology investigation of colorectal cancer on community group in Guangdong province