DEVELOPMENTS OF CARCINOGENESIS INDUCED BY ABNORMALITIES OF WNT GENES

DEVELOPMENTS OF CARCINOGENESIS INDUCED BY ABNORMALITIES OF WNT GENES

Rajendran Prakash

VMKV Engineering College, Periyaseeragapadi, Salem - 636308, Tamil Nadu, India.

ABSTRACT: In cancers, many signals were involved in self-renewal, differentiation and proliferation. Especially, Wnt signaling pathway plays crucial impact in stem cells and cancer development. Wnt genes were involved in the stimulation of Wt signaling pathway in stem cells development. Despite, mutation and overexpression of Wnt genes induced regulation of carcinogenesis. Out of 19 Wnt genes, each Wnt gene has a crucial role in the growth of stem cells and cancer stem cells. In cancer stem cells, aberrant expression of Wnt genes implicated a variety of cancer. Clinical studies, Inhibition of Wnt signaling pathway one of the expensive strategies of cancer therapy. Drugs were developed against cancer development based on inhibition of abnormality of Wnt signaling.

Cancer, Wnt genes, Aberrant expression, Inhibition, Drugs

INTRODUCTION: Since 1982, the int-1 gene was originally identified as a proto-ongogene in mouse mammary tumor and finally called Wnt1 (Wingless int-1). Nowadays, Wnt genes involved in stem cells development and other human disorders ^{1, 2}. Most of the cancers, Wnt genes were expressed aberrantly. Abnormalities of Wnt signaling pathways regulated variety of cancers. Mutations and overexpression of Wnt genes stimulated cell growth, proliferation, and self-renewal of cancer stem cells.

Wnt Genes in Cancer Development: Wnt genes were mutated or highly expressed to the stimulated vast growth of cancer cells. These cells were lead to enormous death rate compare then other diseases. Many types of cancer were stimulated by mutation or overexpression of specific genes.

Abnormalities of Wnt genes were regulated carcinogenesis, and 19 Wnt genes have been the specialized role in cancer development. Each Wnt gene plays a crucial impact in each cancer type ⁵.

Abnormalities of Wnt genes regulated vast cancer development such as breast cancer, endometrial carcinoma, pancreatic adenocarcinoma, prostate cancer, leukemia, melanoma, lung carcinogenesis, medulloblastoma, gastric carcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, Basal cell carcinoma, oral squamous cell carcinoma, head and neck squamous cell carcinoma, bladder cancer, teratocarcinoma, ovarian carcinogenesis and non-small cell lung cancer ^{3, 4}.

Cancer Stem Cells in Breast: Nowadays, breast cancer plays a crucial role in human death, and it occurred mostly in the female. Most of the genes were involved in tumorigenesis and some Wnt genes highly expressed in breast cancer. Wnt1 gene was first identified as an ongogene in mouse mammary tumor ¹. Wnt1 gene highly expressed in breast cancer, and most of the case mutated Wnt1 gene promoted breast cancer. Normally Wnt1 gene has important role in self-renewal and proliferation of stem cells, likewise abnormality of Wnt1 gene regulated self-renewal, differentiation and proliferation of cancer stem cells in the breast. Other all Wnt genes were also regulated breast tumor ⁶.

Cancer Stem Cells in Rectum: Wnt genes were involved in one part of cancer development such some colorectal or colon, or rectal cancer was caused by abnormalities of Wnt genes. Overexpression of Wnt genes such as Wnt1, Wnt2, Wnt3, Wnt6, Wnt9a, Wnt10A, and Wnt16 were induced specialized cancer of colorectal cancer ⁹. Wnt2 gene was highly expressed in colon cancer.

Mutation of Wnt genes such as Wnt5a, Wnt7a, Wnt10B, and Wnt16 have also stimulated the regulation of cancer development in the colon. These Wnt genes were also involved in cancer stem cells self-renewal in rectum ^{8, 10}.

FIG. 1: STIMULATION OF Wnt SIGNALING BY SPECIFIC Wnt GENES. GREEN COLORS INDICATED ONLY Wnt /β-CATENIN SIGNALING GENES (CANONICAL PATHWAY). ORANGE COLORS INDICATED ONLY NON-CANONICAL PATHWAY GENES. RED ACCENT COLORS INDICATED BOTH CANONICAL AND NON-CANONICAL Wnt GENES. A: Diagram shown Wnt/β-catenin signal stimulated by Wnt genes; B: Diagram shown Wnt/PCP signal regulated by Wnt genes; C: Diagram shown Wnt/Ca²⁺ signal induced by Wnt genes.

Cancer Development in the Prostate Gland: In the prostate gland, aberrant expression of Wnt genes was regulated cancer development in male. Prostate cancer one of the critical cancer type because a lot of males died for this cancer ¹¹.

TABLE 1: Wnt GENES IN CANCER DEVELOPMENTS

Many characters were involved in prostate cancer development but most of the prostate cancer regulated by abnormalities of signals, especially Wnt signaling. Aberrant of expression of Wnt genes involved cancer development in prostate gland ¹². Mostly, Wnt1 highly expressed in prostate cancer and other genes such as Wnt3a, Wnt5a, Wnt7b, Wnt11, and Wnt16 were also induced carcinogenesis in the prostate gland. Wnt3a gene was highly expressed in prostate cancer. Other Wnt genes expressions were not studied well in prostate cancer development ¹³.

Vast Cell Growth in Lung Organ: Wnt signals were involved in cell cycle and cell growth. Abnormality of the Wnt signaling pathway regulated enormous cell growth and differentiation. In the lung, Wnt genes were highly expressed and regulated enormous cell growth, and mutation of Wnt genes were expressed in non-small cell lung cancer ¹⁴. Mutated Wnt1 was highly expressed in non-small cell lung cancer, and other types of Wnt genes were also regulated lung cancer such as

Wnt2, Wnt2b, Wnt3, Wnt5a, Wnt7a and Wnt7b. Wnt5a gene was highly expressed in lung cancer ¹⁵.

Other Types of Cancer: In cancer, Wnt genes have stimulated the regulation of a variety of cancer, and some genes were specialized to caused specific cancer type. Wnt1 Wnt2, Wnt5a, Wnt7b, Wnt10a, Wnt10b genes were expressed in esophageal squamous cell carcinoma. Wnt1 and Wnt5a were highly expressed in melanoma ^{22, 44}.

Mutation of Wnt2b, Wnt4, Wnt5a, Wnt10a, and Wnt16 have induced the regulation of cell growth and differentiation in leukemia. In endometrial cancer, Wnt genes have a specialized role in self-renewal of cancer stem cells, and Wnt2, Wnt3, Wnt4, Wnt5a, Wnt7a, Wnt7b, and Wnt10b genes were expressed in endometrial cancer ¹⁶. Wnt9a was reported in acute lymphoblastic leukemia. Epigenetic inactivation of Wnt7a and Wnt9a were recently reported in pancreatic cancer ⁵.

Cancer Treatment: Wnt signals activated in intestinal, prostate and mammary tumor and also implicated in skin cancer, lung cancer, bladder cancer, leukemia, and other cancers. Aberrant expression and mutation of Wnt genes highly stimulated the regulation of various cancers. Therefore inhibition of Wnt signals leads valuable strategies of cancer therapy ¹⁷. Many important drugs were involved in Wnt signals inhibition and also these drugs synthesized as an antagonist of Wnt signals. Anti-cancer drugs such as Non-steroidal anti-inflammatory drugs (NSAIDs), vitamin D and their derivatives, small molecules inhibitors, and antibody-based treatment ^{18, 19}.

NSAIDs has suppressed the activation of cancer reported in colon cancer. Vitamin D was also involved in colon cancer treatment, and it inhibited the activation of β-catenin. Other chemopreventive agents such as curcumin and lycopene also deactivated Wnt signaling pathway ¹⁹.

CONCLUSION: Cancers are one of the critical diseases in our animal kingdom. Many of the cancer was caused by physical, chemical, and biological factors. These all factors were affected the cellular level of function. These functions were stimulated via various signaling pathways.

In cell-cell interaction, signaling pathways were communicated one cell to other cells. Therefore, abnormalities of all signals were regulated a variety of cancer and other disorders.

Among these signals, Wnt signals were regulated both stem cells and cancer stem cells. Especially deregulation of Wnt signals were implicated carcinogenesis.

In cancer, inhibition of Wnt signals important strategies of cancer treatment. Many drugs were synthesized against the abnormalities of the Wnt signaling pathway. But these drugs were killed cancer cells, not cancer stem cells. So, a new herbal product of drugs will use to kill cancer stems cells without side effect.

ACKNOWLEDGEMENT: The author is sincere thank to Dr. A. Nagappan, Principal, Dr. C.K. Hindumathy, Dean- Biosciences and Dr. S. Anandakumar, Vinayaka Mission’s Kirupananda Variyar Engineering College, Salem, Tamil Nadu for their support for carrying out this work.

CONFLICT OF INTEREST: Nil

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    How to cite this article:

    Prakash R: Developments of carcinogenesis induced by abnormalities of Wnt genes. Int J Pharm Sci & Res 2014; 5(9): 3609-15. doi: 10.13040/IJPSR.0975-8232.5(9).3609-15.

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